Blandine Gatta

Fat distribution in obese women is associated with subtle alterations of the hypothalamic–pituitary–adrenal axis activity and sensitivity to glucocorticoids

OBJECTIVES Obesity with abdominal body fat distribution (A‐BFD) and hypothalamic‐pituitary‐adrenal (HPA) axis activity are somehow linked, but the exact interactions still need clarification. Obese subjects display normal circulating plasma cortisol concentrations with normal circadian rhythms. However, when the HPA axis is pharmacologically challenged, body fat distribution matters and then A‐BFD obese women differ from those with subcutaneous body fat distribution (P‐BFD). We hypothesized that lower dose provocative and suppressive tests than those used to diagnose hypercortisolism of tumour origin or adrenal insufficiency would shed some light on the characteristics of the HPA axis activity in relation with body fat distribution.

Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients

BACKGROUND Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood. DESIGN AND METHODS A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly. RESULTS Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CAB(max/w)) was 3.5 mg (2.0-10.5). Despite a higher CAB(max/w) in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CAB(max/w) (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CAB(max/w) or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%). CONCLUSION CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.

Lessons from an unpleasant surprise: a biochemical strategy for the diagnosis of pheochromocytoma.

Objective To audit the performances of the analytes used in the diagnosis of pheochromocytoma and to present a graphical guideline to help the diagnosis. Design A 5 year retrospective study. Settings Laboratory and departments of a university hospital. Participants In-patients, suspected of bearing a pheochromocytoma, were investigated for urinary metanephrines and catecholamines (photometric method) and vanillylmandelic acid, fractionated catecholamines and metanephrines [high pressure liquid chromatography (HPLC) coupled to electrochemical detection (ED)] urinary excretion. Main outcome Patients with a pheochromocytoma (24 out of 2003 patients) were diagnosed by the combination of normetanephrine and metanephrine determination. Results All analytes but dopamine were significantly elevated in patients with a pheochromocytoma. The area under the receiver operating characteristics (ROC) curves were the highest for total metanephrines, normetanephrine and metanephrine determinations. Because of analytical interferences in the metanephrines determination, the normetanephrine and metanephrine performed better. It is noteworthy that all pheochromocytomas had either normetanephrine or metanephrine levels above their respective optimal threshold (sensitivity 100%). The best optimal threshold performance was reached by the mean of three daily samples. Total or fractionated catecholamines or vanillylmandelic acid were less accurate tools. Conclusion Amongst urinary tests, the combined use of HPLC/ED determination of normetanephrine and metanephrine seems the most effective screening strategy for the diagnosis of pheochromocytoma. The older total metanephrine photometric assay is grieved by analytical interferences.

Pilot study of a 10-week multidisciplinary Tai Chi intervention in sedentary obese women.

Objective: Alternative approaches to weight control and physical activity are increasingly needed. Numerous factors influence weight management, including the choice of physical exercise. No study has previously examined the therapeutic effect of a multidisciplinary weight management program incorporating Tai Chi (TC) exercises among sedentary obese women. Design: Randomized intervention trial with blinded medical provider. Setting: In day hospital consultations. Participants: Twenty-one obese women. Intervention: All subjects participated in a 10-week weight management program that was part of usual care and included a hypocaloric balanced diet, a weekly physician/psychologist/dietician group session, and an exercise program. For the exercise component, subjects were randomized to either a 2-hour weekly session of TC or a conventional structured exercise program. Main Outcome Measures: Changes in weight, body composition, heart rate, blood pressure, mobility scores, mood, Three Factor Eating Questionnaire scores, and General Self-Efficacy. Results: The TC arm improved in resting systolic blood pressure, chair rise test, mood, and reduced percent of fat at week 10 and at 6 months follow-up. General self-efficacy was enhanced in both groups and maintained at 30 weeks. Conclusion: The observed benefits over a 30-week period of a multidisciplinary weight management program incorporating TC exercises on physical functioning mood and dietary restraint need further understanding of how sedentary obese women adhere to physical activity like TC or other alternative exercises.

Re-evaluation of the efficacy of the association of cabergoline to somatostatin analogues in acromegalic patients.

Several studies have emphasized the importance of controlling GH and IGF-I secretion in acromegalic patients in order to restore the observed adverse mortality to control rates. 1 Despite controversies about the place of surgery and radiotherapy in the treatment algorithms of acromegaly, antisecretory medications are required in about 50% of patients. 2 Among these, somatostatin analogues (SA) have been the most widely used with a success rate in controlling IGF-I in 60% of patients. 3 The recent availability of the GH receptor antagonist, pegvisomant, offers new perspectives in patients partially resistant to SA. 4 Elsewhere, dopamine agonists (DA) have been shown to be only effective in 10% of acromegaly patients. However, Cozzi et al . recently published in the journal that well-tolerated doses of cabergoline could restore normal IGF-I in acromegalic patients who were only partly responsive to SA. 5

Is bariatric surgery really inefficient in hypothalamic obesity

to tamoxifen alone. The inhibitory effect of androgens on breast cells appears to occur in a dose-dependant manner. Although confounded by the use of gonadotropin-releasing hormone analogue therapy, histological data derived from mastectomies from female-to-male transsexuals exposed to high-dose androgens have demonstrated reduction in glandular tissue in up to 93% of cases. Our case provides clinical evidence that pathologically high levels of androgens cannot only reduce proliferation, but may inhibit normal breast development, despite appropriate pubertal levels of oestrogen and an apparently mature hypothalamic– pituitary–gonadal axis. Thus, it appears that the elevated androgens were having a direct inhibitory effect on the breast tissue. Moreover, the rapid progression of breast development (15 months to attain Tanner 5 breasts, compared with average progression from Tanner 2–4 over 36 months) provides further evidence that removal of the source of the elevated androgens allowed breast development to proceed. Although androgens have been associated with both endometrial atrophy and proliferation, our case provides evidence that high-dose androgens can inhibit endometrial maturation. While at initial presentation, there was no endometrial stripe on ultrasound, postoperatively, with resolution of the hyperandrogenism, regular menses commenced within 2 months. High androstenedione levels have been shown to be a risk factor for primary amenorrhoea and thinner endometrial lining in girls with polycystic ovarian syndrome, supporting the hypothesis that significantly elevated androgens can inhibit the endometrium. In conclusion, our patient, presenting with discordant biochemical and physical signs of puberty, provides unique insight into the potential inhibitory effects of significantly elevated androgens on breast and endometrial maturation.

Bioavailable estradiol in man: Relationship with age and testosterone

Sex hormones undergo decreases in aging men. Several studies have shown the association of low levels of bioavailable estradiol with osteoporosis in man. To allow a better approach of sex hormones influences, we evaluated bioavailable estradiol concentrations in men and its correlation with age and testosterone. We show that bioavailable estradiol decreases significantly with age. We provide reference values in men with normal testosterone levels.

Different methods to estimate serum free cortisol: a comparison during cortisol tetracosactide testing.

Abstract Background: Serum cortisol is routinely quantified by immunoassays. In intensive care units serum free cortisol (FC) determination has been described as a better indicator of survival than total cortisol (TC). To estimate FC different methods are available including saliva sampling. We compared five methods to estimate FC, before and after an ACTH stimulating test in patients suspected of adrenal insufficiency. Method: Serum and saliva was collected from 130 patients from the Endocrine Department of a university hospital before and after tetracosactide injection for TC determination. FC was estimated: after serum ultrafiltration, quadratic (Coolens’) or cubic (Dorin’s) equations, using TC/cortisol-binding globulin concentrations ratio or using cortisol concentration determination in saliva. Results: FC concentrations obtained by different techniques were significantly correlated and Passing-Bablok regressions showed no deviation from linearity between salFC and filtFC or quadFC. Using the routine assumption that the patients were correctly diagnosed using a post-tetracosactide TC threshold of 550 nmol/L the FC methods generating the best ROC curves were salFC and filtFC or cubFC 30 min after tetracosactide injection. Conclusions: FC concentrations obtained by different techniques are significantly but not similarly correlated with TC. As, salFC and filtFC are more convenient to perform than methods involving CBG assays and are better correlated to TC during tetracosactide tests they may be preferred as FC surrogate assays.

Phasing-in plasma metanephrines determination

OBJECTIVES We set up plasma normetanephrine (pNMA) and metanephrine (pMA) assays as they demonstrated their usefulness for diagnosing phaeochromocytomas. Our scope is to describe some practical laboratory aspects and the clinical relevance of these assays in our endocrinological or cardiological departments. METHODS We retrospectively reviewed the results of MA from a population of in- and outpatients over a 7-year period. Subjects (n=2536) from endocrinological or cardiological departments were investigated (66 phaeochromocytomas). Urinary NMA (uNMA) and pNMA, and urinary MA (uMA) and pMA were assayed by HPLC with electrochemical detection. RESULTS pNMA and pMA assays are now more frequently requested than uNMA and uMA. This changed our laboratory work load with improved delivery, sensitivity and reliability of plasma assays as well as reduced apparatus maintenance time. The pNMA and pMA upper reference limits (URLs) of subjects with no phaeochromocytoma were 1040 and 430 pmol/l respectively. Sensitivity and specificity based on receiver operating characteristic curves optimal points were 83 and 93% for pNMA at 972 pmol/l and 67 and 98% for pMA at 638 pmol/l. Sensitivity and specificity of paired tests of pMA (positive test: at least one analyte above its URLs) were 100 and 91% respectively. CONCLUSION The very low concentration of analytes requires a sustained very good apparatus analytical sensitivity. This can be obtained in an up-to-date laboratory. In terms of clinical performances, assays in plasma or urine are equivalent. Depending on local preferences, populations, strategies or departments, requests for one or the other assay may sustain the need for specifically defined reference ranges.