Abdominal fat index by ultrasound does not estimate the metabolic risk factors of cardiovascular disease better than waist circumference in severe obesity.

OBJECTIVE: To evaluate by ultrasound the ratio between preperitoneal (P) and subcutaneous (S) fat (AFI), in quantifying the cardiovascular risk in 258 obese patients (BMI 41.2+/-6.3 kg/m2; age 45.1 +/- 13.6 years). RESEARCH METHODS AND PROCEDURES: Glucose, insulin, lipid profile, uric acid and fibrinogen were measured. HOMA-IR, waist girth, AFI and quartiles of BMI were calculated. RESULTS: AFI lowered with increasing BMI and showed a positive correlation with TGL (r=0.37, P<0.01) and uric acid (r=0.40, P<0.001) in the 1st quartile of BMI (30.2-36.4) and a negative correlation with HDL (r=- 0.32, P<0.001) in the 3rd quartile (40.6-45.1). When BMI exceeded the value of 45.2 kg/m2 these correlations were no longer significant. In all subjects S correlated positively with uric acid (r=0.64, P<0.001), and negatively with HOMA-IR (r=- 0.41, P<0.001) and TGL (r=- 0.35, P=0.02); P correlated positively with CHOL (r=0.48, P=0.04) and TGL (r=0.33, P=0.03), and negatively with HDL (r=- 0.46, P=0.03). Waist girth showed more significant correlations than AFI in the lower quartiles of BMI, but not at the highest one. DISCUSSION: AFI, P and S, as waist girth do not seem to quantify the metabolic risk factors of cardiovascular disease in severe obese subjects, but AFI is probably useful in obese populations with BMI<45 kg/m2, even though not as strong as waist girth.

Weight cycling and cardiovascular risk factors in obesity.

OBJECTIVE: To assess the relationship between weight cycling and some cardiovascular risk factors in a wide sample of obese subjects. DESIGN: Cross-sectional study with retrospective evaluation of weight and dieting history. SUBJECTS: In all, 459 obese subjects, 340 women and 119 men (age: 19-65 y; BMI: 30-69 kg/m2). MEASUREMENTS: Body composition and fat distribution (by bioelectrical impedance analysis and anthropometry), systolic and diastolic blood pressure, plasma glucose, total and HDL cholesterol, triglycerides, insulin and insulin resistance by HOMAir, various weight cycling indices. RESULTS: A positive correlation between weight cycling indices, BMI and percent body fat was found in both genders. Also, the maximum absolute amount of weight regained following a single diet episode was significantly associated to insulin and HOMAir in both genders. However, these correlations disappeared when the data were controlled for age and BMI. CONCLUSION: In obese subjects of both genders weight cycling, and in particular weight regain, does not appear to be associated with adverse effects on body composition, fat distribution or cardiovascular risk factors in an independent manner, but rather in relation to fat accumulation over years.

Subclinical hypothyroidism in obese patients: relation to resting energy expenditure, serum leptin, body composition, and lipid profile.

OBJECTIVE: To evaluate whether subclinical hypothyroidism (SH) affects resting energy expenditure (REE) as well as body composition, lipid profile, and serum leptin in obese patients. RESEARCH METHODS AND PROCEDURES: A total of 108 obese patients with SH defined as normal free thyroxine levels and thyroid-stimulating hormone (TSH) values of > 4.38 microU/ml (mean +/- 2 SD of the values of our reference group of obese patients with normal thyroid function) were compared with a group of 131 obese patients matched for age, sex, and body mass index (BMI) but with normal TSH levels. We assessed estimated daily caloric intake by 7-day recall, REE by indirect calorimetry, body composition by bioelectrical impedance analysis, serum leptin by radioimmunoassay, and lipid profile (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides). RESULTS: All of the variables measured were not different between the euthyroid obese patients and those with SH. In a multiple regression model with REE expressed for kilograms of fat free mass (REE/kgFFM) as a dependent variable and percentage of fat mass, BMI, waist-to-hip ratio, age, TSH, free thyroxine, serum leptin, and caloric intake as independent variables, only percentage of fat mass was significantly correlated with REE/kgFFM in both groups. In the SH group only, BMI, waist-to-hip ratio, age, and TSH were related to REE/kgFFM and explained 69.5% of its variability. After dividing the patients with SH using a cutoff TSH value of 5.7 microU/ml, which represents 3 SD above the mean of TSH levels of the group of obese patients with normal thyroid function, only REE/kgFFM was significantly different and lower in the group of more severely hypothyroid patients. DISCUSSION: In patients with obesity, SH affects energy expenditure only when TSH is clearly above the normal range; it does not change body composition and lipid profile. We suggest that, at least in obese patients, evaluation of TSH levels may be useful to rule out a possible impairment of resting energy expenditure due to a reduced peripheral effect of thyroid hormones.

The A19G polymorphism in the 5' untranslated region of the human obese gene does not affect leptin levels in severely obese patients.

Recently, the presence of different polymorphisms in the regulatory region of the ob gene has been associated with variations in leptin levels. However, the results of these studies are still contradictory. The aim of the present investigation was to evaluate the presence of the A19G polymorphism in an Italian population of obese patients and to verify its association with leptin levels and anthropometric, metabolic, and clinical parameters. Two hundred five obese patients [body mass index (BMI) > 36 kg/m2; 135 women and 70 men; mean age, 46.9+/-14.23 yr] were screened for presence of the polymorphism; 61 normal-weight controls (mean BMI, 21.05 kg/m2; 53 women, 8 men) were also screened to compare polymorphism frequency. For obese patients, BMI, waist-to-hip ratio, resting energy expenditure, body composition, fasting leptin, total cholesterol, high-density lipoproteins, triglycerides, and caloric intake were determined. Genotype frequencies in obese and control subjects were compared using the contingency table chi-square test; in obese subjects an ANOVA was performed to evaluate association between the polymorphism and several clinical parameters. No significant differences in genotype distribution between control and obese subjects were found. No significant correlations were found between this polymorphism and serum leptin levels and the other parameters considered. These findings confirm the results obtained in both a Finnish and a French population; taken together, these observations might rule out a significant role for the A19->G polymorphism in the regulation of leptin levels and other clinical, anthropometric, and metabolic parameters.

Leptin plasma concentrations are dependent on body fat distribution in obese patients.

AIM: To evaluate whether fat distribution plays a role in determining serum leptin concentrations. PATIENTS AND METHODS: One-hundred and forty-seven obese patients, 77 males and 70 females, aged 45.1 +/- 13.2 y (mean +/- s.d.; range 21-73 y), with body mass index (BMI) ranging from 30 to 55 kg/m2 (mean 42.3 +/- 5.9). Ultrasound assessment of the thickness of subcutaneous and preperitoneal fat was carried out and calculation of their ratio as abdominal fat index (AFI), waist-hip ratio (WHR), body composition by bioelectrical impedance to evaluate the percentage of fat mass (FM%) and total amount of fat (FMKg) were also determined. Plasma leptin was measured by radio immuno assay (RIA). RESULTS: In the whole group of patients, serum leptin concentrations were 37.2 +/- 18.4 ng/ml (range 6-101.3 ng/ml); in spite of BMI values not being significantly different, women had leptin values significantly higher (47.4 +/- 17.4 ng/ml) (P < 0.01) than males (28.1 +/- 15.1 ng/ml), also after correction for fat mass. The mean thickness of abdominal subcutaneous fat was 33.7 +/- 12.9 mm and it was significantly (P < 0.001) higher in female (40.9 +/- 10.6 mm) than in male (27.1 +/- 11.2 mm) patients; preperitoneal thickness was 22.9 +/- 7.1 mm, with significantly (P < 0.05) higher values in males (24.2 +/- 6.8 mm) than in females (21.7 +/- 7.3 mm). Accordingly, AFI (in all patients 0.84 +/- 0.6) was significantly higher in males (1.09 +/- 0.6) than in females (0.56 +/- 0.2). In the overall population, leptin concentrations were directly and significantly related to subcutaneous but not preperitoneal fat; they showed a strong inverse relationship with AFI and WHR. When the results were evaluated dividing the patients according to gender, subcutaneous fat thickness showed a stronger association with leptin levels in males than in females, whereas no association was found with preperitoneal fat thickness. Leptin and AFI values were significantly related only in men. WHR values were not correlated with leptin concentrations in either sex. When fat mass was added to the model, subcutaneous fat thickness, AFI and WHR remained independently associated with leptin concentrations. Age and diabetes did not influence these measures. CONCLUSIONS: Fat distribution contributes to the variability in serum leptin in obese patients. In particular, subcutaneous abdominal fat is a determinant of leptin concentration, also independently of the amount of fat mass, whereas the contribution of preperitoneal visceral fat is not significant.

Serum leptin concentration in moderate and severe obesity: relationship with clinical, anthropometric and metabolic factors.

OBJECTIVE: To study clinical, anthropometric and metabolic determinants of serum leptin concentrations in a series of patients with a wide range of obesity. SUBJECTS: 400 patients, 116 males and 284 females, aged 44+/-12.3 years with body mass index (BMI) ranging from 31 to 82 kg/m2 (mean 41.4+/-7.1). MEASUREMENTS: Energy intake by 7-day recall, resting energy expenditure (REE) by indirect calorimetry, body composition determined by bioelectrical impedance; C index, an anthropometric index of abdominal fat distribution, and waist-hip ratio (WHR), blood glucose serum leptin concentrations, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, uric acid, and insulin concentrations HOMA IRI (homeostastis model assessment of insulin resistance index). RESULTS: Leptin concentrations were higher in obese than in normal subjects and in females than in males without differences between diabetic and non-diabetic patients; leptin concentrations were not related to age and showed a strong negative association with energy intake only in the group of women with BMI less than 40. Leptin concentrations showed a direct correlation with BMI and body fat values (expressed either as percentage of total body mass or absolute fat mass) independent of age and sex. After adjustment for fat mass, leptin values higher than predicted were found in women whereas concentrations lower than predicted were found predominantly in men. Leptin showed an inverse correlation with WHR and C-index, the latter persisting also after correction for gender and fat mass. REE, but not REE/kg fat-free mass (FFM) was inversely related to leptin also after correction for sex and absolute fat mass. Leptin concentrations were directly associated with HOMA IRI, insulin and HDL cholesterol and inversely associated with triglycerides and uric acid. The relationship of leptin with HOMA IRI was still evident after adjusting for sex but was lost when absolute fat mass was added to the model; HDL cholesterol and triglycerides appeared to be variables independent of leptin concentrations even when both sex and fat mass were added to the model. CONCLUSIONS: In a large group of obese patients (half of whom had severe obesity, gender, BMI and fat mass accounted for the largest proportion of serum leptin concentrations variability. We found that in obese subjects there is an effect of fat distribution on leptin concentrations and that, after excluding variability due to absolute fat mass, patients with a greater amount of abdominal fat have relatively low leptin concentrations which in turn relates to a metabolic profile compatible with an increased cardiovascular risk. Women with milder obesity may retain some degree of control of food intake by leptin.

Metabolic effects of biosynthetic growth hormone treatment in severely energy-restricted obese women.

OBJECTIVE: Severe energy restriction in the treatment of obesity is limited by catabolism of body protein stores and, consequently, loss of lean as well as fat tissue. Growth hormone (GH), whose secretion is markedly impaired in obesity, is endowed with both lipolytic and protein anabolic properties. The aim of this study was to verify the effects of GH administration on body composition, plasma leptin levels and energy metabolism in obese patients undergoing severe dietary restriction. DESIGN: Single-blind placebo-controlled study. Twenty obese women were fed a diet of 41.86 kJ/kg ideal body weight (IBW) daily for 4 weeks: 10 of them were randomly assigned to a 4 week treatment with biosynthetic GH (rhGH, Saizen, Serono, Rome, Italy), 1 U/kg IBW/week in daily subcutaneous injections; the other 10 patients, matched for age and BMI, received vehicle only. SUBJECTS: Twenty women with simple obesity (age: 25.4+/-1.07 y, BMI: 35.9+/-0.35 kg/m2). MEASUREMENTS: Plasma IGF-I and leptin, serum markers of bone turnover (serum bone isoenzyme of alkaline phosphatase, osteocalcin and urinary hydroxyproline), nitrogen balance, body composition (by DEXA), and resting energy expenditure (REE, by indirect calorimetry) were evaluated at baseline and after 4 weeks. RESULTS: Mean IGF-I plasma levels, not influenced by energy restriction in patients receiving placebo, displayed a significant increase in the group treated with rhGH. The mean weight reduction and fat mass loss were not significantly different in the two groups (6.0+/-0.51 vs 7.2+/-0.30 kg, NS, and 5.36+/-0.460 vs 4.28+/-0.572 kg, NS, with rhGH and placebo, respectively). Likewise, plasma leptin levels decreased significantly in weight-reduced subjects receiving either rhGH (from 16.2+/-2.37 to 6.4+/-0.39 ng/ml, P < 0.05) or placebo (from 14.3+/-2.55 to 7.7+/-3.77 ng/ml, P < 0.05). On the contrary, the mean decrease of lean body mass (LBM) was significantly lower in the GH-treated patients than in those receiving vehicle (1.52+/-0.60 vs 3.79+/-0.45 kg, P < 0.05). In keeping with these findings, the mean daily nitrogen balance was significantly less negative in the GH-treated subjects than in the vehicle-injected patients (mean of the 4 week daily urine collections -185.7+/-40.33 vs -363.9+/-55.47 mmol/d, P < 0.05, respectively). Further, a significant reduction of mean REE was recorded in the energy-restricted placebo-treated patients (from 8807+/-498 to 7580+/-321 kJ/24 h, P < 0.05), but not in the patients receiving rhGH (from 8367+/-580 to 8903+/-478 kJ/24 h, NS). Actually, when corrected for LBM, REE was even increased by GH administration (from 197.9+/-11.76 to 219.3+/-9.87 kJ/kg LBM/24 h, P < 0.05), whereas it was unchanged in the placebo group (from 201.7+/-13.85 to 190.0+/-9.87 kJ/kg LBM/24 h, NS). A tendency of serum markers of bone turnover to increase was observed in the patients treated with rhGH, however with no changes in bone mineral content and density. CONCLUSION: rhGH treatment, though unable to enhance diet-induced weight and fat mass reduction, was effective in stimulating IGF-I production and conserving LBM and increasing its energy metabolism even in the presence of severe energy restriction.

Discriminating between body fat and fluid changes in the obese adult using bioimpedance vector analysis.

OBJECTIVE: Conventional body composition methods may produce biased quantification of fat and fat-free mass in obese subjects, due to possible violation of the assumption of constant (73%) tissue hydration. We used an assumption-free, graphical method for interpreting body weight variation in obesity using bioelectrical measurements. DESIGN: 540 obese subjects with body mass index (BMI) > 31 kg/m2 without apparent edema were compared to 726 healthy subjects with BMI < 31 kg/m2 and to 50 renal patients with apparent edema. A subgroup of 48 obese subjects were evaluated again after weight loss (8.6 kg, 3 BMI units) following one-month energy restriction (5 MJ/d, 1200 kcal/d). 32 obese uremic patients were evaluated before and after a dialysis session (3.2 kg fluid removed). Direct measurements obtained from standard 50 kHz frequency bioelectrical impedance analyzer were used as impedance vectors in the Resistance-Reactance Graph. RESULTS: 1) Impedance vectors of obese subjects could be discriminated from those of edematous patients with 91% correct allocation; 2) A significant lengthening of vectors was observed after fluid loss of 3 kg in obese subjects; but 3) A body weight loss of about 9 kg after energy restriction was associated with no vector displacement. CONCLUSION: A different impedance vector pattern was associated with body weight loss in obesity due to fluid removal (vector lengthening) versus an energy-restricted diet (no vector displacement).

Early postoperative evaluation in patients with Cushing's disease: usefulness of ovine corticotropin-releasing hormone test in the prediction of recurrence of disease.

In the attempt to identify parameters that might predict the risk of recurrence of Cushing's disease at an early stage after successful pituitary microsurgery, we evaluated retrospectively the usefulness of an early postoperative determination of morning plasma and urinary cortisol levels and of adrenocorticotropin (ACTH) and cortisol responses to ovine corticotropin-releasing hormone (oCRH) stimulation in 30 patients with pituitary-driven Cushing's disease followed up for 9 months to 10 years after pituitary surgery. At an early postoperative evaluation, while off substitutive therapy, 30 patients, out of 36 treated by pituitary microsurgery for Cushing's disease, were considered in remission on the basis of subnormal (21 patients), low-normal (eight patients) or normal (one patient) morning plasma and urinary cortisol levels, whereas six patients with supranormal urinary cortisol excretion were considered as surgical failures. The plasma ACTH response to oCRH was subnormal (17 patients) or normal (four patients) in 21 patients (Group 1) and supranormal in nine patients (Group 2). All of the six patients with persistence of Cushing's disease had supranormal ACTH response to oCRH. Basal and oCRH-stimulated cortisol levels were subnormal in 25 out of 30 patients considered in remission. During long-term evaluation, six patients had recurrence of Cushing's disease 9 months to 5 years after surgery; their early postoperative mean basal morning plasma and mean urinary cortisol were higher than those recorded in patients who did not relapse, although a wide overlap between subjects was evident. In five out of these six patients urinary cortisol excretion had decreased to almost undetectable values during low-dose dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)

Memory impairment in Cushing's disease.

In the present study the cognitive performance of 25 patients with Cushing's disease (CD) was extensively evaluated in comparison with normal control subjects, matched one by one. The results indicate a selective impairment of memory functions: the number of patients showing a significantly impaired mnesic performance increases with age. Moreover, the neuropsychological impairment tends to recover in those cases who underwent further controls after surgical treatment. The neuropsychological data are discussed in the light of recent evidence in the literature concerning the effects of adrenal steroids on the brain.

Stimulatory effect of oCRH on alpha-subunit secretion during petrosal sinus sampling in patients with Cushing's disease.

During bilateral and simultaneous venous sampling of the inferior petrosal sinuses for preoperative localization of ACTH secreting microadenomas, alpha-subunit levels, in addition to ACTH, were determined in 9 patients with Cushing's disease. The aim of the study was to evaluate the possible occurrence of unilateral increases of alpha-subunit in basal conditions and the alpha-subunit responsiveness to oCRH. All the patients examined showed a central to peripheral and an intersinus gradient of ACTH concentrations before and/or after oCRH stimulation. Seven patients showed a central to peripheral alpha-subunit gradient in basal conditions. Lateralization of alpha-subunit concentrations was recorded in 4 patients in basal conditions (intersinus gradient > or = 1.55) and paralleled the side with the highest ACTH concentrations. After oCRH stimulation all but one patient showed a unilateral alpha-subunit increase in blood from the inferior petrosal sinus with the highest oCRH stimulated ACTH increase. The present data confirm the occurrence of an increase of alpha-subunit concentration in response to nonspecific stimulation with exogenously administered oCRH, concurrent with an ipsilateral increase of ACTH levels. The mechanism underlying this finding is still unclear, although a paracrine effect from the corticotroph tumour on adjacent pituitary tissue seems so far the most likely explanation.

Inferior petrosal sinus sampling: evidence of a stimulatory effect of oCRH on GH secretion in Cushing's disease.

Preoperative localization of ACTH-secreting microadenomas has been performed in 9 patients with Cushing's disease by using bilateral and simultaneous venous sampling of the inferior petrosal sinuses. In addition to ACTH and PRL we determined GH levels after oCRH stimulation in order to confirm the possible occurrence of unilateral GH increases, as recently observed by us in one patient. A central-to-peripheral and an intersinus gradient of ACTH concentration was observed in all patients examined before and/or after oCRH stimulation. In 7 patients central-to-peripheral and side-to-side PRL gradients were recorded in basal conditions: in 5 of these patients a unilateral oCRH-induced PRL increase was observed. Six out of the 7 patients with unilateral PRL increases also showed an intersinus GH gradient in basal conditions (ratio greater than or equal to 1.5); in 5 of them a clearcut oCRH-induced GH increase was observed. A peripheral oCRH-induced GH and PRL increase was not observed in any of the patients. The observation of a paradoxical oCRH-induced GH increase in the inferior petrosal sinus with the higher ACTH concentration is of speculative and clinical interest; whether it reflects co-secretion of hormones by the tumour or hormone release by non-tumourous cells via paracrine mechanism is still to be clarified. The unilateral GH increase could represent an additional signal of the presence and localization of an ACTH-secreting tumour.

Bilateral and simultaneous venous sampling of inferior petrosal sinuses for ACTH and PRL determination: preoperative localization of ACTH-secreting microadenomas.

We report our experience on venous sampling of the inferior petrosal sinuses for basal and CRH-stimulated ACTH and PRL gradients in 8 patients with surgically proven Cushing's disease who had normal preoperative neuroradiological studies. In 7 patients basal plasma ACTH concentrations in the inferior petrosal sinus ipsilateral to the tumor were higher than in the contralateral sinus; the gradients were enhanced by oCRH administration. In one out of two patients who had previously undergone unsuccessful pituitary microsurgery, neither basal nor oCRH-induced ACTH increases led to correct localization of the microadenoma within the pituitary. In 4 out of 7 patients basal serum PRL concentrations in the inferior petrosal sinus ipsilateral to the tumor were higher than in the contralateral; only two out of 4 showed an increase in PRL levels after oCRH injection. Our study confirms that simultaneous and bilateral venous sampling of inferior petrosal sinuses is a valuable means to identify the site of microadenomas in patients with Cushing's disease without neuroradiological evidence of the tumor. This procedure may give misleading results in patients previously operated on. Unilateral or predominant increases of PRL concentration during catheterization of the inferior petrosal sinuses, when present, always lateralize to the side of the corticotroph adenoma, providing a possible additional signal of the presence of the tumor.

Size reduction of an ACTH-secreting pituitary macroadenoma in Nelson's syndrome by sodium valproate: effect of withdrawal and re-institution of treatment.

We describe herein the reduction in the size of an ACTH-secreting pituitary macroadenoma in a patient with Nelson's syndrome during chronic administration of sodium valproate, and the changes in tumour volume after withdrawal and re-institution of treatment. The patient had elevated plasma ACTH levels (1123-1255 pmol/l), which increased markedly after CRH stimulation. A first 4-month course of sodium valproate administration (600 mg/day, orally) was started. Plasma ACTH fell to 550-726 pmol/l with persistence of responsiveness to CRH; brain computed tomography showed a clearcut reduction of tumour size. One month after drug withdrawal, the tumour volume appeared unchanged and plasma ACTH values ranged between 374 and 440 pmol/l. One and a half year after drug withdrawal, a brain computed tomography showed re-expansion of the pituitary adenoma with evidence of suprasellar extension, which had never been seen previously. Plasma ACTH ranged between 113 and 199 pmol/l. A second course of sodium valproate was started; after three months, a brain computed tomography documented clearcut reduction of tumour volume from a suprasellar extension to a partially empty pituitary fossa. Plasma ACTH ranged from 396 to 542 pmol/l with persistence of responsiveness to CRH. The present report documents for the first time the reduction of tumour size in a patient with an ACTH-secreting macroadenoma by chronic administration of sodium valproate.

Use of ketoconazole in the treatment of Cushing's syndrome.

The therapeutic value of ketoconazole for long term treatment of patients with Cushing's syndrome was studied. Seven patients with Cushing's disease and one with an adrenal adenoma received 600-800 mg/day ketoconazole for 3-13 months. Plasma ACTH, cortisol, and dehydroepiandrosterone sulfate levels and urinary cortisol, 17-ketosteroid, and tetrahydro-11-deoxycortisol excretion were determined periodically during the treatment period. Plasma ACTH and cortisol responses to CRH stimulation were determined before and during treatment. Rapid and subsequently persistent clinical improvement occurred in each patient; plasma dehydroepiandrosterone sulfate and urinary 17-ketosteroid and cortisol excretion decreased soon after the initiation of treatment, subsequently remaining normal or nearly so throughout the treatment period. Urinary tetrahydro-11-deoxycortisol excretion increased significantly. Plasma cortisol levels decreased. Plasma ACTH levels did not change, and individual plasma ACTH and cortisol increments in response to CRH were comparable before and during treatment. The cortisol response to insulin-induced hypoglycemia improved in one patient and was restored to normal in another. The seven patients tested recovered normal adrenal suppressibility in response to a low dose of dexamethasone during ketoconazole treatment. Ketoconazole is effective for long term control of hypercortisolism of either pituitary or adrenal origin. Its effect appears to be mediated by inhibition of adrenal 11 beta-hydroxylase and 17,20-lyase, and it, in some unknown way, prevents the expected rise in ACTH secretion in patients with Cushing's disease.

Transsphenoidal microsurgery for Cushing's disease.

The study shows the results of transsphenoidal microsurgery in 23 patients with Cushing's disease (CD). Out of the 21 patients with tumour confined to the sella, 18 who had selective adenomectomy, and 1 who underwent total hypophysectomy had correction of hypercortisolism. None of the patients with extrasellar extension of the tumour was cured. In 2 cases no adenoma was found intra-operatively. Post-operative hypoadrenalism was documented in all the patients who remitted clinically. By 3-26 months after surgery, adequate cortisol secretion was found in 12 patients, nine of whom regained diurnal variation of cortisol secretion and ten cortisol responsiveness to hypoglycaemia; a normal or near normal response of cortisol to CRF was documented in 11 out of 17 patients tested. Thyroid and gonadal function was restored in all but two patients in clinical remission, whereas GH responsiveness to hypoglycaemia appeared impaired in 11. Two patients had recurrence of the disease 2 and 3 years, respectively, after successful adenomectomy. In our experience transsphenoidal selective adenomectomy is an effective treatment for most patients with CD; additional therapeutic approaches should be considered for patients bearing pituitary tumours with extrasellar extension, whose surgical outcome is often disappointing.

Lack of ACTH lowering effect of sodium valproate in patients with ACTH hypersecretion.

The effect of an oral dose of 200 or 400 mg sodium valproate (DPA) on ACTH and cortisol secretion was assessed in 11 patients with Cushing's disease (3 bilaterally adrenalectomized), 3 patients with Nelson's syndrome and 6 patients with Addison's disease. In none of the patients examined DPA induced changes in ACTH (and cortisol) levels appreciably different from the fluctuations recorded after placebo administration. The effect of a long term administration of sodium valproate (600-1000 mg/day) was evaluated in 2 patients with active Cushing's disease and in 1 patient with Nelson's syndrome (3 weeks, 3, 9 months respectively); in the 2 patients with Cushing's disease ACTH and cortisol secretion, 17-hydroxy-corticosteroids (17-OHCS) urinary excretion did not change during DPA treatment. Similarly the cortisol response to hypoglycemia and the 17-OHCS urinary excretion after dexamethasone were not normalized. Long term DPA administration did not induce either clinical or hormonal modifications in the patient with Nelson's syndrome. These findings do not support the possibility that a deficiency of a GABAergic system plays a role in the pathogenesis of ACTH hypersecretion. DPA does not seem to be of therapeutical value in the medical management of Cushing's disease and Nelson's syndrome.

Cushing's disease and marked hyperprolactinemia in a patient with a pituitary macroadenoma: effectiveness of bromocriptine treatment.

The case of a young boy bearing a pituitary PRL secreting adenoma (20-30,000 ng/ml) with the unusual association of clinical and endocrinological features of Cushing's disease successfully treated with bromocriptine is described. Brain computed tomography evidenced a huge pituitary adenoma leading to visual field defects and raised intracranial pressure. Due to the very large size of the tumor, which rendered the complete neurosurgical removal unlikely, medical treatment with bromocriptine (10 mg/day) was started. Follow-up for more than six months demonstrated an impressive reduction of tumor size, the lowering of prolactin levels into the normal range, the normalization of visual field, and the regression of both clinical and biochemical signs of hypercortisolism.