Loss of pons-to-hypothalamic white matter tracks in brainstem obesity.

Hyperphagia and obesity have been reported following damage to the hypothalamus in humans. Other brain sites are also postulated to be involved in the control of food intake and body weight regulation, such as the amygdala and brainstem. The brainstem, however, is thought to primarily integrate short-term meal-related signals but not affect long-term alterations in body weight, which is controlled by higher centers. The objective of this study was to identify structural pathways damaged in a patient with a brainstem cavernoma who experienced sudden onset of hyperphagia and >50 kg weight gain in <1 year following surgical drainage via a midline suboccipital craniotomy. Diffusion tensor imaging revealed loss of nerve fiber connections between her brainstem, hypothalamus and higher brain centers with preservation of motor tracks. Imaging and endocrine testing confirmed normal hypothalamic structure and function. Gastric bypass surgery restored normal appetite and body weight to baseline. This is the first report of 'brainstem obesity' and adds to the brain regions that can determine the long-term body weight set point in humans.

Health status, mood, and cognition in experimentally induced subclinical thyrotoxicosis.

OBJECTIVE: Our objective was to determine whether subclinical thyrotoxicosis alters health status, mood, and/or cognitive function. DESIGN: This was a double-blinded, randomized, cross-over study of usual dose l-T(4) (euthyroid arm) vs. higher dose l-T(4) (subclinical thyrotoxicosis arm) in hypothyroid subjects. PATIENTS: A total of 33 hypothyroid subjects receiving l-T(4) were included in the study. MEASUREMENTS: Subjects underwent measurements of health status, mood, and cognition: Short Form 36 (SF-36); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, and Digit Span Backwards), and motor learning (Pursuit Rotor). These were repeated after 12 wk on each of the study arms. RESULTS: Mean TSH levels decreased from 2.15 to 0.17 mU/liter on the subclinical thyrotoxicosis arm (P < 0.0001), with normal mean free T(4) and free T(3) levels. The SF-36 physical component summary and general health subscale were slightly worse during the subclinical thyrotoxicosis arm, whereas the mental health subscale was marginally improved. The POMS confusion, depression, and tension subscales were improved during the subclinical thyrotoxicosis arm. Motor learning was better during the subclinical thyrotoxicosis arm, whereas declarative and working memory measures did not change. This improvement was related to changes in the SF-36 physical component summary and POMS tension subscales and free T(3) levels. CONCLUSIONS: We found slightly impaired physical health status but improvements in measures of mental health and mood in l-T(4) treated hypothyroid subjects when subclinical thyrotoxicosis was induced in a blinded, randomized fashion. Motor learning was also improved. These findings suggest that thyroid hormone directly affects brain areas responsible for affect and motor function.

Health status, mood, and cognition in experimentally induced subclinical hypothyroidism.

OBJECTIVE: The objective of the study was to determine whether subclinical hypothyroidism causes decrements in health status, mood, and/or cognitive function. DESIGN: This was a double-blinded, randomized, crossover study of usual dose l-thyroxine (L-T4) (euthyroid arm) vs. lower dose L-T4 (subclinical hypothyroid arm) in hypothyroid subjects. PATIENTS: Nineteen subjects on L-T4 therapy for primary hypothyroidism participated in the study. MEASUREMENTS: Subjects underwent measurements of health status, mood, and cognition using validated instruments: Short Form 36, Profile of Mood States, and tests of declarative memory (paragraph recall, complex figure), working memory (N-back, subject ordered pointing, digit span backward), and motor learning (pursuit rotor). The same measures were repeated after 12 wk on each of the study arms. RESULTS: Mean TSH levels increased to 17 mU/liter on the subclinical hypothyroid arm (P < 0.0001). Mean free T4 and free T3 levels remained within the normal range. The Profile of Mood States fatigue subscale and Short Form 36 general health subscale were slightly worse during the subclinical hypothyroid arm. Measures of working memory (N-back, subject ordered pointing) were worse during the subclinical hypothyroid arm. These differences did not depend on mood or health status but were related to changes in free T4 or free T3 levels. There were no decrements in declarative memory or motor learning. CONCLUSIONS: We found mild decrements in health status and mood in L-T4-treated hypothyroid subjects when subclinical hypothyroidism was induced in a blinded, randomized fashion. More importantly, there were independent decrements in working memory, which suggests that subclinical hypothyroidism specifically impacts brain areas responsible for working memory.

Central nervous system vasculitis caused by propylthiouracil therapy: a case report and literature review.

Antineutrophil cytoplasmic antibodies (ANCA) are associated with vasculitis, including vasculitis induced by drugs such as the thionamides. The affected organ systems in thionamide-induced vasculitis have been primarily renal, musculoskeletal, and dermatologic. We describe the first case of thionamide-induced central nervous system vasculitis presenting as confusion, with complete resolution after discontinuation of propylthiouracil. We review the literature and summarize 42 additional cases of thionamide-induced ANCA-positive vasculitis since 1992. Propylthiouracil was responsible in 93% of cases and the predominant ANCA pattern on immunofluorescent staining was perinuclear (p-ANCA). Clinical improvement occurred after drug discontinuation in 93%, steroid therapy was used in some cases. The mean duration of treatment with thionamides was 35 months prior to presentation. Long-term medical treatment with thionamides for hyperthyroidism may increase the risk of this severe side effect.

Variable effects of nonsteroidal antiinflammatory agents on thyroid test results.

To investigate the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on thyroid tests, 25 healthy subjects underwent a single-dose study and/or a 1-wk study. In the single-dose study, subjects received a single dose of one of six NSAIDs (aspirin, salsalate, meclofenamate, ibuprofen, naproxen, or indomethacin) at 0800 h. Total and free thyroid hormones and TSH were analyzed 0, 1, 2, 3, 4, and 8 h later. In the 1-wk study, subjects received one of six NSAIDs for 7 d. Thyroid hormones and TSH were analyzed at 0800 h each day. Total T(4) and total T(3) were measured by RIA, free T(4) and free T(3) were measured by equilibrium dialysis, and TSH was measured by immunometric assay. There were no changes in any hormones after a single dose or 1 wk of ibuprofen, naproxen, or indomethacin. Single-dose aspirin or salsalate decreased, whereas meclofenamate increased, various total and free thyroid hormone measurements. One week of aspirin or salsalate decreased total T(4), free T(4) (salsalate only), total T(3), free T(3), and TSH. These data confirm that aspirin, salsalate, and meclofenamate affect total and free thyroid hormone measurements and identify three NSAIDs that did not change thyroid tests. TSH remained within the normal range during acute or 1-wk administration of all of the NSAIDs.

Effects of cocaine on basal and pulsatile prolactin levels in rhesus monkeys.

OBJECTIVES: Cocaine abuse is often associated with reproductive cycle dysfunction including altered menstrual cyclicity and decreased ovulation rates. Cocaine might also alter prolactin (PRL) secretion, presumably through the effects of this drug on hypothalamic dopamine, the primary factor regulating pituitary PRL secretion. We assessed basal and pulsatile PRL levels to determine whether hyperprolactinemia is associated with cocaine-induced disruption of menstrual cyclicity in rhesus monkeys. METHODS: Normally cycling, drug-naïve monkeys were studied. Cocaine-treated animals were pair-fed with controls to minimize cocaine-related differences in caloric intake. Twenty-eight monkeys were randomized to receive daily intravenous (iv) infusion of saline or cocaine (1, 2, or 4 mg/kg) on cycle days 2-14. Daily blood samples were obtained through indwelling catheters for measurement of ovarian steroids, gonadotropins, and PRL. Laparoscopy was performed 2 days after the midcycle estradiol surge to document ovulation. Sixteen other monkeys were randomized to receive daily iv infusion of saline or cocaine (4 mg/kg). Blood samples were obtained every 15 minutes for 8 hours in the early (cycle day 1-5), mid- (cycle day 6-10), and late (cycle day 11-15) follicular phase. Plasma was assayed for PRL, and pulses were identified by cluster analysis. RESULTS: All seven control monkeys had laparoscopically confirmed ovulation compared to two of seven monkeys receiving 1 mg/kg, three of seven monkeys receiving 2 mg/kg, and one of seven receiving 4 mg/kg of cocaine hydrochloride. Cycle length was normal in six of seven controls, and in one of seven, two of seven, and two of seven monkeys receiving the 1, 2, and 4 mg/kg of cocaine, respectively. Estradiol levels were significantly higher in controls versus cocaine-treated monkeys, but there was no difference in basal gonadotropin levels during treatment. Mean PRL levels during treatment were significantly lower (P <.05) in controls (4.6 +/- 0.2 ng/mL) as compared to monkeys receiving 1 (6.5 +/- 0.6 ng/mL), 2 (6.1 +/- 0.4 ng/mL), and 4 mg/kg (7.2 +/- 0.6 ng/mL) of cocaine. There was no significant difference in PRL pulse amplitude or frequency between controls and cocaine-treated monkeys during each cycle phase. CONCLUSIONS: Circulating PRL levels were slightly higher in monkeys receiving cocaine during the follicular phase. Although this increase was statistically significant, PRL levels remained well within the euprolactinemic range in cocaine-treated monkeys.

Effects of metyrapone administration on thyrotropin secretion in healthy subjects--a clinical research center study.

Although pharmacological doses of glucocorticoids suppress TSH secretion, less is known regarding the effects of physiological variations in cortisol levels on TSH. To study this issue, 12 healthy subjects each underwent 2 studies, in random order: 1) each subject received an infusion of saline for 48 h; and 2) each subject received an infusion of saline and oral administration of metyrapone (500 mg every 4 h) for 48 h. Cortisol and TSH levels were measured every 15 min during the final 24 h of each study, and resulting mean hormone levels during the 24-h periods were compared between the two studies. Metyrapone administration reduced serum cortisol levels by 39% between 0800 and 1345 h and by 47% between 0200 and 0745 h, with no significant changes during other time periods. Metyrapone increased daytime (0800-1945 h) mean TSH levels by 35%, with no change in nocturnal (2000-0745 h) TSH levels. This led to equalization of daytime and nocturnal TSH levels and abolition of the usual circadian variation in TSH. TSH pulse frequency was no different between the two studies, whereas daytime TSH pulse amplitude increased 33% during metyrapone administration. There were no changes in TSH responses to TRH, or in serum T3 or free T4 levels, at the end of the studies. These results suggest that the early morning increase in endogenous cortisol levels in healthy subjects causes the daytime decrease in TSH levels. In addition, these results show that very mild changes in cortisol levels within the physiological range are sufficient to affect TSH secretion.

Effects of variations in physiological cortisol levels on thyrotropin secretion in subjects with adrenal insufficiency: a clinical research center study.

Although pharmacological doses of glucocorticoids suppress TSH secretion, less is known regarding the effects of physiological variations in cortisol levels on TSH. To study this issue, seven subjects with primary adrenal insufficiency each underwent four studies. In the first study subjects received infusions of saline for 48 h (baseline study). In the second study subjects received infusions of hydrocortisone for 48 h in a pulsatile and diurnal pattern that replicated serum cortisol levels in healthy subjects (physiological study). In most cases, the dose of hydrocortisone was 19 mg/24 h, but this was adjusted as necessary until the resulting serum cortisol levels reproduced those seen in healthy, nonstressed control subjects. In the third study subjects received the same total dose of hydrocortisone as in the physiological study, but with pulses of equal magnitude spaced evenly throughout the time period (constant study). In the fourth study subjects received the same total dose of hydrocortisone, but with the diurnal pattern shifted 12 h from the physiological infusion (reversed study). TSH levels were measured every 15 min during the final 24 h of each study. During the baseline study, the 24-h mean TSH level was 2.87 +/- 0.56 mU/L and did not exhibit any diurnal variation. During the physiological study, daytime TSH levels decreased 39% compared to those during the baseline study due to decreased TSH pulse amplitude, and the normal TSH diurnal rhythm was reestablished. The constant and reversed studies did not lead to significant changes in serum TSH levels compared to baseline. These results suggest that the normal circadian variation in endogenous cortisol levels may control TSH secretion, with maximal TSH suppression seen during the time when cortisol levels are highest. However, changing the diurnal pattern of hydrocortisone infusion did not lead to reciprocal changes in TSH levels, and the specific nature of the interactions between cortisol and TSH within the physiological range remains to be fully elucidated.

Cortisol production rates in subjects with suspected Cushing's syndrome: assessment by stable isotope dilution methodology and comparison to other diagnostic methods.

It can be difficult to establish the diagnosis of Cushing's Syndrome (CS) in patients with mild or nonspecific clinical and biochemical findings, because available diagnostic tests have limited predictive values. We hypothesized that measurement of 24-h cortisol production rates (CPRs) might be a more sensitive indicator of CS in such patients. We measured CPRs in 28 patients with suspected CS (but equivocal biochemical findings) and in 22 healthy control subjects, by infusing tracer amounts of deuterated cortisol, with simultaneous measurements of 24-h urine free cortisol (UFC) levels; and we frequently sampled serum cortisol levels. CPRs were calculated from the ratio of isotopic enrichment to isotopic dilution of cortisol measured by gas chromatography-negative ion chemical ionization mass spectrometry. Nine of the patients proved to have CS by surgery (CS-Yes), whereas 19 patients were determined not to have CS by biochemical testing (CS-No). Mean 24-h UFCs, nocturnal serum cortisol levels, and CPRs were higher in CS-Yes, compared with CS-No and normal subjects. However, one CS-Yes patient had a normal 24-h UFC, two had normal nocturnal serum cortisol levels, and two had normal 24-h CPRs. There was extensive overlap in all of the biochemical parameters between the CS-Yes and the CS-No groups. Thus, measurement of CPR does not seem to offer any diagnostic advantage over available tests for the diagnosis of CS. Patients with proven CS can have normal UFC levels, normal CPRs, or normal nocturnal cortisol levels, whereas patients not thought to have CS may have elevated levels of any one or more these parameters.

Growth hormone (GH) secretion in primary adrenal insufficiency: effects of cortisol withdrawal and patterned replacement on GH pulsatility and circadian rhythmicity.

We studied the effects of cortisol withdrawal and patterned replacement upon spontaneous GH secretion and circadian rhythmicity in 7 patients with Addison's disease. Hydrocortisone was administered in physiological daily total dosages, and all resulting plasma cortisol values were 2-15 micrograms/dl. It was given in 3 pulsatile modes: simulating "physiological" rhythm, "reverse" diurnal rhythmicity and "continuous" pulsatility. All modes of cortisol administration increased mean 24 h, GH pulse amplitude and interpulse GH levels. During saline infusions circadian GH rhythmicity was preserved, with GH being at its highest between 2400-0400 h. Administration of hydrocortisone in any mode did not modify circadian GH rhythmicity. We conclude: Cortisol replacement in physiological daily doses increases GH output in patients with Addison's disease by augmenting GH pulse amplitude and interpulse levels. This is likely due to the attenuation of hypothalamic somatostatin (SRIF) secretion by physiologic levels of cortisol. By inference, it implies that cortisol deficiency leads to diminution of GH output with low GH pulse amplitude, likely as a result of an augmented hypothalamic somatostatin secretion. However, circadian rhythmicity of GH secretion is glucocorticoid-independent.

A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer.

Recombinant human TSH has been developed to facilitate monitoring for thyroid carcinoma recurrence or persistence without the attendant morbidity of hypothyroidism seen after thyroid hormone withdrawal. The objectives of this study were to compare the effect of administered recombinant human TSH with thyroid hormone withdrawal on the results of radioiodine whole body scanning (WBS) and serum thyroglobulin (Tg) levels. Two hundred and twenty-nine adult patients with differentiated thyroid cancer requiring radioiodine WBS were studied. Radioiodine WBS and serum Tg measurements were performed after administration of recombinant human TSH and again after thyroid hormone withdrawal in each patient. Radioiodine whole body scans were concordant between the recombinant TSH-stimulated and thyroid hormone withdrawal phases in 195 of 220 (89%) patients. Of the discordant scans, 8 (4%) had superior scans after recombinant human TSH administration, and 17 (8%) had superior scans after thyroid hormone withdrawal (P = 0.108). Based on a serum Tg level of 2 ng/mL or more, thyroid tissue or cancer was detected during thyroid hormone therapy in 22%, after recombinant human TSH stimulation in 52%, and after thyroid hormone withdrawal in 56% of patients with disease or tissue limited to the thyroid bed and in 80%, 100%, and 100% of patients, respectively, with metastatic disease. A combination of radioiodine WBS and serum Tg after recombinant human TSH stimulation detected thyroid tissue or cancer in 93% of patients with disease or tissue limited to the thyroid bed and 100% of patients with metastatic disease. In conclusion, recombinant human TSH administration is a safe and effective means of stimulating radioiodine uptake and serum Tg levels in patients undergoing evaluation for thyroid cancer persistence and recurrence.

Levels of leptin during hydrocortisone infusions that mimic normal and reversed diurnal cortisol levels in subjects with adrenal insufficiency.

Levels of leptin throughout the day follow a circadian pattern, with a trough in the late morning/early afternoon and a peak at midnight. This pattern of appearance of leptin correlates inversely with the circadian appearance of cortisol. Pharmacological doses of cortisol increase leptin messenger RNA expression in vitro and raise plasma leptin levels in animals and humans. To determine whether the circadian appearance of leptin might be accounted for by delayed effects from physiological cortisol secretion on fat cells, seven subjects with confirmed adrenal failure were admitted to the Clinical Research Center, on three separate dates, to receive 48-h infusions of: continuous normal saline (NS), a normal daily amount and diurnal pattern of cortisol (ND), and a normal daily amount but reversed diurnal pattern of cortisol. Blood samples were taken every 15 min during the second 24 h of infusion and pooled for hourly measurements of leptin. The circadian pattern of leptin appearance was unchanged during all of the infusion protocols. Area-under-the-curve analysis showed no differences in the total amount of leptin during the NS and ND protocols (20,565 ng/mL x 24 h vs. 20,637 ng/mL x 24 h during NS and ND protocols, respectively; P = 0.94). Acute changes in physiological levels of cortisol do not affect the circadian appearance of leptin in subjects with adrenal failure, nor is cortisol required to maintain normal leptin levels for up to 72 h. The circadian variation of leptin levels cannot be accounted for by normal activity of the hypothalamic-pituitary-adrenal axis.

Cortisol production rate measurement by stable isotope dilution using gas chromatography-negative ion chemical ionization mass spectrometry.

Presented here is a stable isotope dilution technique for determining cortisol production rate (CPR). The method involves extraction and derivatization of cortisol isoforms from serum (0.5 ml), separation of derivatives by gas chromatography, and detection by using negative ion chemical ionization mass spectrometry. This method provides 50-100-fold greater sensitivity than positive ion mass spectrometry and allows for estimations of cortisol production rate with the use of small amounts of pooled serum, even in the presence of high concentrations of lipophilic contaminants. The area under the curve for the total selected ion chromatogram of fluoroacyl derivatives of cortisol (d0, m/z 782) and deuterated cortisol (d3, m/z 785) were used to determine the isotopic dilution ratio in three types of samples: 1) standards: d0/d3 ratios ranging from 1 to 8%; 2) controls: d3-cortisol added to serum with known cortisol concentration; 3) subjects: 24-h pooled serum samples (q 30 min over 24 h) from healthy children (male 10-13 years; female 7-11 years) receiving continuous infusions of d3-cortisol at 2-4% of their estimated CPR. Recovery after the solid phase extraction and derivatization process was >90%, as determined by thin-layer chromatography. Expected versus measured ratios for d3/d0 in standards and serum controls were highly correlated (r2(standard) = 0.99; r2(control) = 0.99) over a wide range of d3-cortisol enrichment (1.0-10.0%). Mean 24-h CPRs were 4.8 +/- 0.6 mg/m2/24 h (mean +/- SEM, n = 7) in male children and 4.4 +/- 0.5 mg/m2/24 h in female children (n = 4). These CPR values are lower than those derived by radio tracer methods, but are in agreement with previous isotopic dilution studies. This technique is an important tool for assessing CPRs in a wide range of disease states affecting cortisol production.

Cavernous sinus sampling is highly accurate in distinguishing Cushing's disease from the ectopic adrenocorticotropin syndrome and in predicting intrapituitary tumor location.

Inferior petrosal sinus sampling (IPSS) is used to distinguish pituitary Cushing's disease from occult cases of the ectopic ACTH syndrome, but is limited in that it requires the use of ovine CRH (oCRH) and is not highly accurate at predicting the intrapituitary location of tumors. This study was designed to determine whether cavernous sinus sampling (CSS) is as safe and accurate as IPSS, whether CSS can eliminate the need for oCRH stimulation, and whether CSS can accurately predict the intrapituitary location of tumors. Ninety-three consecutive patients with ACTH-dependent Cushing's syndrome were prospectively studied with bilateral, simultaneous CSS before and after oCRH stimulation. Prediction of a pituitary or ectopic ACTH source was based on cavernous/peripheral plasma ACTH ratios. Intrapituitary tumor location was predicted based on lateralization (side to side) ACTH ratios. These predictions were compared to surgical outcome in the 70 patients who had surgically proven pituitary (n = 65) or ectopic (n = 5) disease. CSS distinguished pituitary Cushing's disease from the ectopic ACTH syndrome in 93% of patients with proven tumors before oCRH administration and in 100% of patients with proven tumors after oCRH. It was as safe and efficacious as published IPSS results. CSS accurately predicted the intrapituitary lateralization of the tumor in 83% of all patients and 89% of those patients with good catheter position and symmetric venous flow. CSS is as safe and accurate as IPSS for distinguishing patients with pituitary Cushing's disease from those with the ectopic ACTH syndrome. In addition, CSS appears to be superior to IPSS for predicting intrapituitary tumor lateralization.

Reverse transcription polymerase chain reaction analysis of pituitary hormone, Pit-1 and steroidogenic factor-1 messenger RNA expression in pituitary tumors.

Pit-1 is a transcription factor that appears early in embryonic pituitary gland formation and is necessary for the development of somatotropes, lactotropes and thyrotropes. Steroidogenic factor-1 (SF-1) is another early appearing transcription factor that is involved in the development of gonadotropes. In this study we have compared RT-PCR analysis of hormone mRNA with traditional IHC for classification of 27 pituitary tumors and have evaluated the correlation of Pit-1 and SF-1 mRNA with hormone mRNA. RT-PCR detected concordant hormone mRNA in 100% of GH IHC positive, 100% of PRL IHC positive, 33% of TSH IHC positive, and 93% of gonadotropin IHC positive tumors. IHC, however, was concordant in only 71% of GH mRNA positive, 78% of PRL mRNA positive, 17% of TSH beta mRNA positive, and 76% of FSH beta mRNA positive tumors. Pit-1 mRNA was positive in 87% of tumors in which mRNA for GH, PRL or TSH beta was detected and in only 17% of GH, PRL and TSH beta mRNA negative tumors. SF-1 mRNA was positive in 94% of tumors in which mRNA for FSH beta was present and in no FSH beta mRNA negative tumors. We conclude that RT-PCR analysis of hormone mRNA may be more sensitive than traditional hormone IHC for classification of pituitary tumors. Furthermore, tumor Pit-1 mRNA positively correlates with GH, PRL and TSH beta mRNA while tumor SF-1 mRNA correlates well with FSH beta mRNA. Combined analysis of hormone and transcription factor mRNA in pituitary tumor tissue may therefore be a more meaningful approach to pituitary tumor characterization.

Cocaine impairs follicular phase pulsatile gonadotropin secretion in rhesus monkeys.

OBJECTIVE: To assess cocaine's effect on follicular phase pulsatile gonadotropin secretion in normally cycling rhesus monkeys. METHODS: Sixteen monkeys were paired by body weight and randomized to receive intravenous saline (n = 8) or cocaine (4 mg/kg, n = 8) daily on cycle days 2 to 14. Monkeys were chronically cannulated to allow frequent blood collections without anesthesia. Blood samples were obtained every 15 minutes for 8 hours in early (EFP; cycle days 1 to 5), mid-(MFP; cycle days 6 to 10), and late (LFP; cycle days 11 to 15) follicular phase. Plasma concentrations of LH, FSH, and estradiol-17 beta (E2) were determined by radioimmunoassay. Pulses were identified by cluster analysis. Statistical differences were determined by analysis of variance (ANOVA) and Sidak's multiple comparison test. RESULTS: Seven out of eight monkeys in the control group demonstrated timely ovulation. Only one monkey in the cocaine-treated group ovulated. Similar gonadotropin pulse intervals (70 to 90 minutes) were observed throughout the follicular phase in both the controls and cocaine-treated monkeys. LH and FSH pulse amplitudes increased significantly from the EFP/MFP to the LFP in controls. In cocaine-treated monkeys, gonadotropin pulse amplitudes remained at EFP/MFP levels throughout the study period. The mean gonadotropin pulse amplitude and the mean E2 levels in the LFP were significantly greater in controls as compared with cocaine-treated monkeys (P < .001). CONCLUSION: These findings demonstrate that cocaine suppresses the normal increase in LH and FSH pulse amplitude seen in the LFP. Further studies are in progress to determine the mechanism of cocaine's disruption of the hypothalamic-pituitary-ovarian axis.

Subclinical thyroid disease in the elderly.

The development of sensitive assays for thyrotropin (TSH) has led to the discovery that many older patients have abnormal TSH levels without other alterations in serum thyroid hormone levels, conditions termed subclinical hypothyroidism (isolated elevation of TSH levels) and subclinical hyperthyroidism (isolated suppression of TSH levels). Subclinical hypothyroidism occurs in 5% to 10% of elderly subjects, and is especially prevalent in elderly women. Subclinical hyperthyroidism is less common, affecting less than 2% of the elderly population. The causes of subclinical thyroid disease in the elderly are similar to those of thyroid disease in the general population, although medications and iodine-containing compounds may play an increased role. Potential risks of subclinical hypothyroidism in the elderly include progression to overt hypothyroidism, cardiovascular effects, hyperlipidemia, and neurological and neuropsychiatric effects. Potential risks of subclinical hyperthyroidism in the elderly include progression to overt hyperthyroidism, cardiovascular effects (especially atrial fibrillation), and osteoporosis. Decisions to treat elderly subjects with subclinical thyroid disease should be based on a careful assessment of these risks in the individual patient.

Hyperthyroidism due to lymphoma involving the thyroid gland in a patient with acquired immunodeficiency syndrome: case report and review of the literature.

A 31-year old woman with acquired immunodeficiency syndrome (AIDS) and a history of lymphoma presented with a 2-week history of severe hyperthyroid symptoms and new-onset neck swelling. On physical examination, she was found to be clinically hyperthyroid, with a markedly enlarged, diffuse, tender goiter. Thyroid function testing confirmed hyperthyroidism. The patient had a rapidly deteriorating clinical course and died within days of her presentation. At autopsy, near-complete replacement of the thyroid gland with anaplastic large cell lymphoma was found, without coexisting infectious or autoimmune processes in the gland. This is the first case report of a patient with AIDS developing symptomatic thyroid involvement by lymphoma, and one of only a few case reports of hyperthyroidism associated with lymphoma in general.

Thyrotropin levels during hydrocortisone infusions that mimic fasting-induced cortisol elevations: a clinical research center study.

Both short term fasting and administration of high doses of glucocorticoids lead to marked suppression of serum TSH levels in healthy subjects. However, it is not known whether the more mild serum cortisol elevations seen during fasting can account for fasting-induced TSH suppression. To study this question, eight healthy subjects each underwent three 2-day studies: 1) baseline (adlibitum diet), 2) fasting (56 h of total caloric deprivation), 3) hydrocortisone (HC) infusions at a dose and pulsatile pattern that reproduced cortisol levels measured during each subject's fasting study. Subjects required 34-46 mg HC/24 h to achieve these cortisol levels. During each study, blood samples were drawn every 15 min during the final 24 h for serum cortisol and TSH levels. A TRH stimulation test was performed at the end of each study. By design, fasting and HC infusions induced similar mild increases in 24-h serum cortisol levels (32% over baseline), with the most significant increases seen between 1400-0200 h. Fasting decreased 24-h mean and pulsatile TSH levels 65% from baseline, whereas HC infusions decreased mean and pulsatile TSH levels 51% from baseline. Daytime (0800-0200 h) TSH levels were identical in the two studies, whereas nocturnal (0200-0800 h) TSH levels during HC infusions fell midway between baseline and fasting studies. Serum total T3 and TSH responses to TRH were decreased to a similar degree by fasting or HC infusions. These results suggest that mild elevations in endogenous cortisol levels may mediate at least in part fasting-induced changes in TSH secretion and thyroid hormone levels. In addition, these data show that near-physiological doses of HC and resulting changes in serum cortisol levels within the normal range can cause significant decreases in serum TSH levels.