Harmonizing light transmission aggregometry in the Netherlands by implementation of the SSC-ISTH guideline.

Light transmission aggregometry (LTA) is considered the gold standard method for evaluation of platelet function. However, there are a lot of variation in protocols (pre-analytical procedures and agonist concentrations) and results. The aim of our study was to establish a national LTA protocol, to investigate the effect of standardization and to define national reference values for LTA. The SSC guideline was used as base for a national procedure. Almost all recommendations of the SSC were followed e.g. no adjustment of PRP, citrate concentration of 109 mM, 21 needle gauge, fasting, resting time for whole blood and PRP, centrifugation time, speed and agonists concentrations. LTA of healthy volunteers was measured in a total of 16 hospitals with 5 hospitals before and after standardization. Results of more than 120 healthy volunteers (maximum aggregation %) were collected, with participating laboratories using 4 different analyzers with different reagents. Use of low agonist concentrations showed high variation before and after standardization, with the exception of collagen. For most high agonist concentrations (ADP, collagen, ristocetin, epinephrine and arachidonic acid) variability in healthy subjects decreased after standardization. We can conclude that a standardized Dutch protocol for LTA, based on the SSC guideline, does not result in smaller variability in healthy volunteers for all agonist concentrations.

How predictive are sex and empathizing-systemizing cognitive style for entry into the academic areas of social or physical sciences?

Based on the Empathizing-Systemizing (E-S) theory, it was hypothesized that the underrepresentation of female students in the physical sciences and the underrepresentation of males in the social sciences relates to differences in E-S cognitive style between the sexes. This hypothesis was tested in 115 physical science students and 155 social science students from a university in the Netherlands. The students completed visuospatial tests and the systemizing quotient-revised (SQ-R) as measures for systemizing, and a Cartoon Prediction test and the empathy quotient (EQ) as measures for empathizing. Independent of sex, the physical science students scored significantly lower than social science students on EQ (with large effect size) and 'brain type' that represents the standardized difference score between EQ and SQ-R (with large effect size). Physical science students, furthermore, scored significantly higher on the Cartoon Prediction task and one of the visuospatial tasks; however, these effects were only small of size. Unlike the scores on the SQ-R and the performance tests, the 'brain type' score of the EQ and SQ-R questionnaires was a good predictor of entry into social or physical sciences. Interestingly, the typical sex differences in more empathizing and less systemizing in females compared to males were only small for EQ and 'brain type', and absent for the SQ-R and the performance tests. This study only partially confirms the E-S theory, because typical sex differences were only minor in this selective sample and only the self-report measures predicted academic area in the absence of a role for sex.

Blink rate and blink timing in children with ADHD and the influence of stimulant medication.

Spontaneous eye blink rate is modulated by task demands and internal state, and is demonstrated to reflect central dopamine activity. Also, spontaneous eye blinks are strategically timed around salient stimuli. This study investigates whether children with attention deficit hyperactivity disorder (ADHD) show reduced blink rates, blink modulation and blink timing, and whether this is influenced by stimulant medication. The electrooculogram was measured in 18 typically developing children, 16 children with ADHD off methylphenidate (Mph), and 16 children with ADHD on Mph during a rest period and during performance of a 60-min visual selective attention task. Blink rate and timing was extracted from the electrooculogram. No evidence was found for aberrant blink rate or blink modulation in children with ADHD off Mph. All groups increased blink rates from rest to task, and no group differences were found in blink rate during rest and task, or in the modulation of blink rate from rest to task. Time-on task resulted in a similar increase in blink rates in all three groups. Stimulant medication appeared not to influence blink rate and blink modulation, except that in the ADHD off Mph group the blink rate was enhanced only under conditions with performance feedback. All groups inhibited blinks before stimulus presentation and strategically timed their blinks after the stimulus. Children with ADHD off Mph showed reduced blink inhibition before the stimulus; however, given the low incidence (<1 % of the trials) and long latency this is not likely to impair their visual intake.

Neuronal damage biomarkers in the identification of patients at risk of long-term postoperative cognitive dysfunction after cardiac surgery.

Biomarkers of neurological injury can potentially predict postoperative cognitive dysfunction. We aimed to identify whether classical neuronal damage-specific biomarkers, including brain fatty acid-binding protein, neuron-specific enolase and S100 calcium-binding protein ß, as well as plasma-free haemoglobin concentration as a measure of haemolysis, could be used to predict the risk of long-term cognitive decline after coronary artery bypass grafting with or without cardiopulmonary bypass. We assessed cognitive function using the CogState brief computerised cognitive test battery at 3 months and at 15 months after surgery. Blood samples were obtained pre-operatively, after sternal closure, and at 6 h and 24 h postoperatively. We found signs of cognitive decline at 3 months in 15 of 57 patients (26%), and in 13 of 48 patients (27%) at 15 months. Brain fatty acid-binding protein was already significantly higher before surgery in patients with postoperative cognitive dysfunction at 15 months, with pre-operative plasma levels of 22.8 (8.3-33.0 [0-44.6]) pg.ml-1 compared with 9.7 (3.9-17.3 [0-49.0]) pg.ml-1 in patients without cognitive dysfunction. This biomarker remained significantly higher in patients with cognitive decline throughout the entire postoperative period. At 3 months after surgery, high levels of plasma-free haemoglobin at sternal closure were associated with a negative influence on cognitive performance, as were high baseline scores on neuropsychological tests, whereas a higher level of education proved to beneficially influence cognitive outcome. We found that postoperative cognitive dysfunction at 3 months was associated with cognitive decline at 15 months after surgery, and served as a valuable prognostic factor for declines in individual cognitive performance one year later. Classical neuronal injury-related biomarkers were of no clear prognostic value.

Parkinson's patients' executive profile and goals they set for improvement: Why is cognitive rehabilitation not common practice?

Impairments in executive functions (EF) are the core cognitive impairment in patients with Parkinson's disease (PD). Surprisingly, cognitive rehabilitation is not routinely offered to patients with PD. However, in patients with acquired brain injury (ABI), cognitive rehabilitation, in particular strategic executive training, is common practice and has been shown to be effective. In this study, we determined whether PD patients have different needs and aims with regard to strategic executive training than ABI patients, and whether possible differences might be a reason for not offering this kind of cognitive rehabilitation programme to patients with PD. Patients' needs and aims were operationalised by individually set goals, which were classified into domains of EF and daily life. In addition, patients with PD and ABI were compared on their cognitive, in particular EF, profile. Overall, PD patients' goals and cognitive profile were similar to those of patients with ABI. Therefore, based on the findings of this study, there is no reason to assume that strategic executive training cannot be part of standard therapy in PD. However, when strategic executive training is applied in clinical practice, disease-specific characteristics need to be taken into account.

A pilot study of cerebral tissue oxygenation and postoperative cognitive dysfunction among patients undergoing coronary artery bypass grafting randomised to surgery with or without cardiopulmonary bypass*.

Coronary artery bypass surgery, performed with or without cardiopulmonary bypass, is frequently followed by postoperative cognitive decline. Near-infrared spectroscopy is commonly used to assess cerebral tissue oxygenation, especially during cardiac surgery. Recent studies have suggested an association between cerebral desaturation and postoperative cognitive dysfunction. We therefore studied cerebral oxygen desaturation, defined as area under the cerebral oxygenation curve < 40% of > 10 min.%, with respect to cognitive performance at 4 days (early) and 3 months (late) postoperatively, compared with baseline, using a computerised cognitive test battery. We included 60 patients, of mean (SD) age 62.8 (9.4) years, scheduled for elective coronary artery bypass grafting, who were randomly allocated to surgery with or without cardiopulmonary bypass. Cerebral desaturation occurred in only three patients and there was no difference in cerebral oxygenation between the two groups at any time. Among patients who received cardiopulmonary bypass, 18 (62%) had early cognitive decline, compared with 16 (53%) in the group without cardiopulmonary bypass (p = 0.50). Three months after surgery, 11 patients (39%) in the cardiopulmonary bypass group displayed cognitive dysfunction, compared with four (14%) in the non-cardiopulmonary bypass group (p = 0.03). The use of cardiopulmonary bypass was identified as an independent risk factor for the development of late cognitive dysfunction (OR 6.4 (95% CI 1.2-33.0) p = 0.027. In conclusion, although cerebral oxygen desaturation was rare in our population, postoperative cognitive decline was common in both groups, suggesting that factors other than hypoxic neuronal injury are responsible.

Financial dissatisfaction in people with psychotic disorders - A short report on its prevalence and correlates in a large naturalistic psychosis cohort.

Psychotic disorders have a strong negative impact on multiple aspects of daily life, including people's financial situation. This exploratory study examines the level of financial dissatisfaction and its correlates in a large cohort of people with psychotic disorders. Data from the first assessments of people with psychotic disorders (n = 5271) who were included in the Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS; 2006-2020), which is conducted in the northern Netherlands, were used. The Manchester Short Assessment of Quality of Life (MANSA) was used to measure financial dissatisfaction. In addition, sociodemographic and psychiatric characteristics, substance use and global and social functioning were assessed. One-fifth to one-third of people with psychotic disorders report financial dissatisfaction, fluctuating over the year in which they were assessed. These proportions are considerably higher than in the general population. Cannabis and other substance use were associated with higher levels of financial dissatisfaction (small to medium effect). The other significant associations showed (very) small effect sizes. Therefore, we conclude that financial dissatisfaction in people with psychotic disorders appears to be relatively independent of other demographic and psychiatric characteristics, and global and social functioning. These findings are an important first step for increasing knowledge on financial dissatisfaction among people with psychotic disorders. The findings can also contribute to raising awareness about the topic for healthcare professionals working in this field.

Antinuclear autoantibodies are more prevalent in COPD in association with low body mass index but not with smoking history.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a higher prevalence of antinuclear autoantibodies (ANAs). However, a significant subgroup of patients is ANA negative. It remains to be determined which patient groups carry autoantibodies. METHODS: The association of smoking behaviour, disease status, gender, age and body mass index (BMI) with the presence of autoantibodies in the serum was determined in 124 patients with COPD and 108 non-COPD control subjects. In addition, the role of B cells in autoantibody generation in COPD was investigated by sequencing the antibody repertoire of B cells in the lungs of patients with COPD and of ex-smoking and never-smoking control subjects. RESULTS: Patients with COPD had a significantly higher risk of being serum positive for ANAs (OR 3.12, 95% CI 1.68 to 5.76, p<0.001). ANAs were not significantly associated with age, smoking status, gender or pack-years of smoking. Within the COPD population, subjects with BMI <22 kg/m2 had a significantly higher risk of ANAs (OR 4.93, 95% CI 1.50 to 16.50, p=0.009) than those with normal or high BMI. The antibody repertoire of B cells in the lungs of patients with COPD had a high frequency of positively charged CDR3 residues, a feature which is associated with self-reactive antibodies. CONCLUSION: The results show that COPD is a heterogeneous disease with respect to the prevalence of ANAs. ANAs are primarily associated with the presence of COPD and with low BMI, but not with smoking and forced expiratory volume in 1 s.

Strain-specific immunomodulatory effects of Lactobacillus plantarum strains on birch-pollen-allergic subjects out of season.

BACKGROUND: Allergic diseases are increasing world-wide, and according to the hygiene hypothesis may be related to a decreased exposure to environmental bacteria. Probiotic bacteria are recognized for their immunomodulating properties, and may benefit allergy patients. In vitro studies reveal immunomodulatory effects that are strain dependent. Differential immunomodulatory in vitro capacities cannot be extrapolated directly to in vivo efficacy. Thus, in vitro screening should preferably be followed by a comparative analysis of the selected immunomodulatory strains in an in vivo setting. OBJECTIVE: We selected five Lactobacillus strains on their IL-10-inducing capacity, and evaluated the immunomodulatory properties in birch-pollen-allergic subjects outside the hayfever season, with a reduction of IL-13 as the primary outcome. METHODS: A double-blind, placebo-controlled parallel study was performed in which 62 subjects with a proven birch-pollen allergy consumed one of five different probiotic yoghurts containing four Lactobacillus plantarum strains and one Lactobacillus casei strain or a placebo yoghurt. Blood samples were collected at the start and after 4 weeks. Several immune parameters were determined in serum and peripheral blood mononuclear cell cultures (PBMC) derived from these subjects. Results A decrease in birch-pollen-specific IgE was found for four probiotic strains. L. casei Shirota reduced the number of CD16(+) /CD56(+) cells in peripheral blood mononuclear cells. For strain L. plantarum CBS125632, the decrease in IgE coincided with significant decreases in IL-5 and IL-13 production by αCD3/αCD28-stimulated PBMC cultures. CONCLUSION AND CLINICAL RELEVANCE: Subjects with seasonal allergy can be used to determine immunomodulatory responses outside the pollen season within a 4-week study period. L. plantarum CBS125632 decreased several immune markers related to allergy, and may have the potential to alleviate the severity of seasonal allergy symptoms.

Effect of roasting on the allergenicity of major peanut allergens Ara h 1 and Ara h 2/6: the necessity of degranulation assays.

BACKGROUND: Peanuts are often consumed after roasting, a process that alters the three-dimensional structure of allergens and leads to Maillard modification. Such changes are likely to affect their allergenicity. OBJECTIVE: We aimed to establish the effect of thermal treatment mimicking the roasting process on the allergenicity of Ara h 1 and a mix of 2S albumins from peanut (Ara h 2/6). METHODS: Ara h 1 and Ara h 2/6 were purified from raw peanuts and heated in a dry form for 20 min at 145°C in the presence (R+g) or absence (R-g) of glucose, and soluble proteins were then extracted. Sera obtained from 12 well-characterized peanut-allergic patients were used to assess the IgE binding and degranulation capacities of the allergens. RESULTS: Extensive heating at low moisture resulted in the hydrolysis of both Ara h 1 and Ara h 2/6. However, in contrast to Ara h 2/6, soluble R+g Ara h 1 formed large aggregates. Although the IgE-binding capacity of R+g and R-g Ara h 1 was decreased 9000- and 3.6-fold, respectively, compared with native Ara h 1, their capacity to elicit mediator release was increased. Conversely, both the IgE-binding capacity and the degranulation capacity of R-g Ara h 2/6 were 600-700-fold lower compared with the native form, although the presence of glucose during heating significantly moderated these losses. CONCLUSIONS AND CLINICAL RELEVANCE: Extensive heating reduced the degranulation capacity of Ara h 2/6 but significantly increased the degranulation capacity of Ara h 1. This observation can have important ramifications for component-resolved approaches for diagnosis and demonstrates the importance of investigating the degranulation capacity in addition to IgE reactivity when assessing the effects of food processing on the allergenicity of proteins.

Weight loss in obese men by caloric restriction and high-dose diazoxide-mediated insulin suppression.

OBJECTIVE: To examine the concept whether high-dose diazoxide (DZX)-mediated insulin suppression, in combination with moderate caloric restriction and increased physical activity, can establish a weight loss of at least 15% in obese hyperinsulinaemic men. DESIGN: Open, uncontrolled, 6-month pilot study. Energy intake was reduced by 30%, and walking for at least 30 min a day was strongly recommended. DZX treatment was started at 50 mg t.i.d. and increased by 50 mg per dose every 4 weeks to a maximum of 300 mg t.i.d., unless hyperglycaemia or other side-effects occurred. SUBJECTS AND METHODS: Eighteen obese hyperinsulinaemic men with a body mass index of 30-35 kg/m(2). Measurements included body weight, body composition, blood pressure, glycaemic control, insulin response, adiponectin and serum lipids. RESULTS: Body weight decreased by 9.4 kg (95% CI: 5.6-13.2 kg, p < 0.001), waist circumference reduced by 9.2 cm (95% CI: 5.3-12.9 cm, p < 0.001) and total body fat mass decreased by 23.3% (95% CI: 13.7-32.9%, p < 0.001), without a concomitant change in soft tissue lean body mass or bone mass. Fat loss was inversely related to fasting insulin levels achieved at 6 months (r = -0.76, p < 0.002). Diastolic blood pressure decreased by 10.9 mmHg (95% CI: 6.5-15.4 mmHg, p < 0.002). Fasting and postmeal peak insulin levels were reduced by about 65% (p < 0.001) and decreased to the normal range for non-obese men. Fasting and postmeal peak glucose levels increased by 0.8 +/- 0.3 mmol/l (p = 0.01) and 1.4 +/- 0.7 mmol/l (p = 0.06) respectively. Haemoglobin A1c rose by 0.5% to 5.9 +/- 0.2%. CONCLUSION: High-dose DZX-mediated insulin suppression, in combination with moderate caloric restriction and lifestyle advice, is associated with a clinically relevant degree of weight reduction. A more extensive exploration is warranted to optimize this mode of treatment and to further clarify its risks and benefits.

The assessment of depression in Parkinson's disease.

BACKGROUND: Motor symptoms form the hallmark of Parkinson's Disease (PD), although features like depression are often present. Depression rating scales [e.g. Montgomery-Asberg Depression Rating Scale (MADRS)] used in PD measure affective, cognitive and somatic symptoms. An important clinical question is which items of the MADRS are likely to be influenced by PD symptoms. METHODS: Depression was assessed in 43 PD patients who scored below the cut-off of the MADRS and who differed widely in motor severity. RESULTS: Parkinson's Disease patients scored relatively highest on Concentration difficulties, Reduced sleep and Inner tension. Reduced sleep, Lassitude and Suicidal thoughts were associated with motor severity and specifically with Bradykinesia, Rigidity and Axial impairment, however not with Tremor. To avoid a possible influence on our results of coincidentally included PD patients with a depression, all associations between somatic MADRS items and motor severity were corrected for the influence of affective symptoms of depression. All associations remained significant. DISCUSSION: In conclusion, the items Reduced sleep and Lassitude of the MADRS are likely to be influenced by motor symptoms. The high score on Concentration difficulties is suggested to be a reflection of cognitive dysfunction in PD. Thus, when assessing depression in PD, using a depression rating scale like the MADRS, adjusted cut-off scores are required.

High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment.

BACKGROUND: Obesity can be associated with biochemical evidence of isolated hypogonadotropic hypogonadism (IHH) in men. Prevalence and severity of IHH in obese men are not exactly known. OBJECTIVE: To assess the prevalence of IHH in obese men. DESIGN AND SUBJECTS: Cross-sectional study of 160 obese men, BMI >30 kg/m2, who applied for medical or surgical treatment of obesity in a general teaching hospital. MAIN OUTCOME MEASURES: Total and calculated free testosterone (TT and FT) in relation to body mass index (BMI). RESULTS: Mean age of the study population was 43.3 +/- 0.8 years (mean +/- SEM), BMI ranged from 30.0 to 65.7 kg/m2. TT and FT levels were inversely related to BMI (-0.48, p<0.0001). Total testosterone was subnormal in 57.5% and free testosterone in 35.6% of the subjects. The group of men with IHH was more obese, had higher Hba IC levels and had a 2.6 higher risk for cardiovascular disease. Decreased libido and erectile dysfunction were 7.1 and 6.7 times as common in IHH than in eugonadal obese men. CONCLUSION: Reduced T levels, well into the hypogonadal range, are common in male obesity. Assessment of its clinical implications, and a search for the best mode of treatment are warranted.

1H NMR T1 relaxation rate study on substrate orientation of fluoromethylanilines in the active sites of microsomal and purified cytochromes P450 1A1 and 2B1.

The present study describes 1H NMR T1 relaxation rate studies on fluoromethylanilines bound to the active sites of microsomal and purified cytochromes P450 1A1 and 2B1. From the data obtained, insights into the average orientation of the substrates with respect to the paramagnetic Fe3+ centre in the cytochromes P450 could be derived. Particular attention was paid to a possible extra relaxation pathway for methyl protons compared to the aromatic protons, due to the rotational motion of the CH3 around the sigma-C-CH3 bond. However, this effect appeared to be minimal and to result in at most a few percent underestimation of the actual distance of the methyl protons to the Fe3+ centre. Furthermore, the data obtained demonstrate that all aromatic protons are at about the same average distance from the paramagnetic centre. The results also demonstrate that the fluromethylanilines are bound to the active sites of cytochromes P450 1A1 and 2B1 in a similar way. A time-averaged orientation of the substrate with the Fe3+ above the aromatic ring, with the pi-orbitals of the aromatic ring and those of the porphyrin rings in a parallel position, providing possibilities for energetically favourable pi-pi interaction defines the orientation which best fits the results of the present study. Possibilities for a flip-flop rotation around an axis in the plane of the aromatic ring can be included in this picture, as such rotations would still result in a similar average distance of all aromatic protons to the Fe3+ paramagnetic centre. The results obtained also indicate that possible differences in metabolite patterns resulting from conversion of the fluoromethylanilines by different cytochromes P450, especially P450 1A1 and 2B1, are unlikely to be caused by a specific orientation of the substrate imposed by the substrate binding site of the enzyme.

Interaction between the substrate and the high-valent-iron-oxo porphyrin cofactor as a possible factor influencing the regioselectivity of cytochrome P450 catalysed aromatic ring hydroxylation of 3-fluoro(methyl)anilines.

In the present study the in vitro and in vivo aromatic ring hydroxylation of a series of amino and/or methyl containing fluorobenzenes, i.e. 3-fluoro(methyl)anilines, was investigated and compared to the calculated density distribution of the reactive frontier pi-electrons of the aromatic substrate. This was done (1) to study to what extent the regioselectivity of the aromatic ring hydroxylation of the 3-fluoro(methyl)anilines could be predicted on the basis of the calculated chemical reactivity, as was previously observed for a series of fluorinated benzenes and monofluoroanilines, and (2) to investigate which factors contribute to possible deviations from the predictions on the basis of the calculated chemical reactivity. Results obtained show that the in vitro and in vivo aromatic ring hydroxylation of the series of 3-fluoro(methyl)anilines correlates qualitatively with the calculated frontier orbital density distribution for electrophilic attack by the cytochrome P450(FeO)3+ species. These results indicate that the HOMO/HOMO-1 frontier orbital densities, i.e. the chemical reactivity of the carbon centres for an electrophilic attack, predict the preferential as well as the non-reactive sites for cytochrome P450 catalysed aromatic ring hydroxylation of the tested model compounds. The absolute values, however, deviated in a systematic way; C4 para hydroxylation being observed to a higher extent than expected on the basis of chemical reactivity and C2/C6 ortho hydroxylation being observed to a lower extent than expected. Additional experiments were performed using different microsomal preparations and microperoxidase-8. The latter is a mini-heme protein of eight amino acids without a substrate binding site. In incubations of the model compounds with different types of microsomal preparations, as well as with MP-8 and purified reconstructed cytochrome P4502B1, similar systematic deviations between the predicted and observed regioselectivity of aromatic hydroxylation were observed. These results show that the regioselectivity of aromatic ring hydroxylation of the 3-fluoro(methyl)anilines cannot be predominantly ascribed to an interaction between the substrate and the substrate binding site of the cytochromes P450 dictating a specific stereoselective positioning of the substrate in the active site. More likely, the systematic deviations between the observed and predicted regioselectivity of hydroxylation of the tested model substrates should be ascribed to an (orienting) interaction between the substrate and the activated cytochrome P450(FeO)3+ cofactor.

Glycaemic control without weight gain in insulin requiring type 2 diabetes: 1-year results of the GAME regimen.

INTRODUCTION: Weight gain appears to be unavoidable in patients with type 2 diabetes who are switched from oral agents to insulin therapy. Peripheral hyperinsulinism induced by the use of long-acting insulin may be the key to explain this adverse effect. AIM: The aim of this study was to investigate whether a regimen free of long-acting insulin can provide long-term glycaemic control without causing weight gain. PATIENTS AND METHODS: This is an uncontrolled, 1-year study comprising 58 patients with type 2 diabetes and secondary failure, age 30-75 years, BMI 25-35 kg/m(2), HbA1c > 7.5% and fasting C-peptide level > 0.3 mmol/l. All patients were treated with the GAME regimen, a combination of glimepiride administered at 20:00 hours for nocturnal glycaemic control, insulin aspart three times daily for meal-related glucose control and metformin. RESULTS: Seventy-one per cent of the patients were considered evaluable. HbA1c decreased from 10.0 +/- 0.3 to 7.4 +/- 0.1% (p < 0.001). Fifty-nine per cent reached HbA1c levels

Letrozole normalizes serum testosterone in severely obese men with hypogonadotropic hypogonadism.

BACKGROUND: Morbid obesity is associated with increased estradiol production as a result of aromatase-dependent conversion of testosterone to estradiol. The elevated serum estradiol levels may inhibit pituitary LH secretion to such extent that hypogonadotropic hypogonadism can result. Normalization of the disturbed estradiol-testosterone balance may be beneficial to reverse the adverse effects of hypogonadism. AIM: To examine whether aromatase inhibition with Letrozole can normalize serum testosterone levels in severely obese men with hypogonadotropic hypogonadism. PATIENTS AND METHODS: Ten severely obese men, mean age 48.2 +/- 2.3 (s.e.) years and body mass index 42.1 +/- 2.6 kg/m(2), were treated with Letrozole for 6 weeks in doses ranging from 7.5 to 17.5 mg per week. RESULTS: Six weeks of treatment decreased serum estradiol from 120 +/- 20 to 70 +/- 9 pmol/l (p = 0.006). None of the subjects developed an estradiol level of less than 40 pmol/l. LH increased from 4.5 +/- 0.8 to 14.8 +/- 2.3 U/l (p < 0.001). Total testosterone rose from 7.5 +/- 1.0 to 23.8 +/- 3.0 nmol/l (p < 0.001) without a concomitant change in sex hormone-binding globulin level. Those treated with Letrozole 17.5 mg per week had an excessive LH response. CONCLUSION: Short-term Letrozole treatment normalized serum testosterone levels in all obese men. The clinical significance of this intervention remains to be established in controlled, long-term studies.