Leptin, insulin and TNF-alpha in weight loss.

Forty-eight morbidly obese patients were placed on a very low calorie (800 kcal) formula diet (OPTIFAST) for a 10-week period with the goal of achieving 10% weight loss within this time. Weekly serum leptin measurements were performed to determine whether changes in this adipose protein would serve as a useful marker of acute and chronic weight loss compliance. In the basal state, serum leptin averaged 56.9 +/- 5.8 ng/ml (SE) in the 24 successful (S) patients, and 67.7 +/- 6.7 ng/ml in the non-successful (N-S) group. During the first week of weight loss there was little change in leptin despite an average weight loss of 2.2%, but after 4 weeks serum leptin decreased by 36% in the S group, and 20% in the N-S group. After 10 weeks, the S group averaged 13.6% weight loss and the serum leptin decreased to 50% of starting levels. In the 24 N-S patients, the mean weight loss was 7.0%, and serum leptin decreased by 22%, remaining unchanged in the final 6 weeks despite a weight loss of 3.6% in this time. On a week-to-week basis serum leptin changed concordantly with weight loss only two-thirds of the time. In a subgroup of 14 patients (8 S+6 N-S), serial assessments of serum leptin, insulin and tumor necrosis factor-alpha (TNF-alpha) were performed. Serum insulin levels decreased with weight loss similar in magnitude to that noted for leptin; however, the insulin changes occurred more rapidly. Serum TNF-alpha also decreased with weight loss, but the weekly changes were more erratic, with a concordance rate of only 48%. In summary, serum leptin, insulin and TNF-alpha all decreased during a rapid weight loss program but at differing rates and variability, precluding their usefulness as markers of week-to-week weight loss compliance.

Adrenocortical carcinoma: clinical and laboratory observations.

BACKGROUND: The clinical features and natural history of adrenocortical carcinoma are highly dependent on the type of center reporting their experience. Observations from oncology services suggest a high incidence of nonfunctioning tumors, whereas reports from endocrine clinics emphasize excessive corticoid and androgen production in the majority of tumors. The incidence rate and natural history of childhood adrenal carcinoma generally has been under emphasized. METHODS: Over the past 17 years, the authors have evaluated and treated 47 patients with adrenocortical carcinoma referred to the University of Sao Paulo, 22 of whom were children. RESULTS: There is a bimodal age incidence of adrenal carcinoma, with the disease peaking in the first and fourth decades of life. Childhood adrenal carcinoma is characterized by a high rate of incidence of virilization, marked overproduction of androgens, and a less aggressive clinical course, and appears to be more amenable to surgical and other therapeutic modalities. By contrast, adrenocortical carcinoma occurring in adults presents more commonly as a mixed Cushing and virilizing syndrome, with overproduction of corticoids and androgens and a far more aggressive clinical course, leading to rapid death within months or years. Nonfunctioning adrenocortical carcinoma is less common; it generally occurs in older adults and exhibits a rapid downhill course. Modern day imaging methods have improved the diagnosis and staging of adrenal carcinoma greatly. In the authors' experience, the histologic criteria of Weiss appeared to predict tumor prognosis most accurately, whereas immunologic markers, cytoskeletal markers, DNA ploidy, cell phase markers, and oncogenic probes have yielded inconsistent results to date. Surgical removal of a localized tumor remains the best hope for long term survival. Medical therapy with mitotane and its successors in patients with Stage III or IV (MacFarlane system as modified by Sullivan et al.) disease appear to have added little to longevity or quality of life. CONCLUSIONS: When diagnosed in children, adrenal carcinoma is associated with virilism and a less aggressive natural history; however, when it occurs in adults, the disease presents more commonly as a mixed Cushing-virilizing syndrome and has a virulent course. The Weiss histologic criteria appear to correlate best with disease prognosis, but other histochemical, cell cycle, and genetic markers have not, to date, aided in disease management.

The effects of spironolactone on testosterone fractions and sex-hormone binding globulin binding capacity in hirsute women.

This study explored the effect of the anti-androgen spironolactone on sex-hormone binding globulin (SHBG) and the distribution of circulating testosterone (T) into various free and bound fractions in seven women with hirsutism assessed before and then monthly for three months on a regimen of spironolactone, 100 mg bid as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgen parameters and serum T fractions studies. None of the women were judged obese based upon body mass index values. After three months of spironolactone therapy, there was little change in the hirsutism index, and measurement of serum T, androstenedione, DHEA-S and 17 beta-estradiol showed no significant changes, the same occurring with SHBG-binding capacity. However, there was a shift in the distribution of circulating T, with a decrease in SHBG-bound T and an increase in albumin-bound and free T (non-SHBG-bound fractions). As previous reports suggest that non-SHBG-bound fractions represent bioavailable fractions, the current data suggests that T fraction studies may not be clinically useful parameters of hyperandrogenism in women receiving antiandrogen therapy.

Ectopic ACTH syndrome.

Ectopic ACTH syndrome represents a cancer-induced amplification of a property [proopiomelanocortin (POMC) peptides production] normally present in the cells from which the cancer originated but with aberrant posttranslational processing of POMC resulting in a greatly elevated secretion of ACTH precursors. The classic ectopic ACTH-producing tumors described in the 1960s were highly malignant but more recently slowly growing tumors such as carcinoids are reported with increasing frequency. Clinical features of patients with ectopic ACTH were analyzed, including biochemical abnormalities, plasma ACTH, cortisol and urinary steroids. Dynamic tests such as high-dose dexamethasone suppression, metyrapone and ovine-CRH (oCRH) stimulation were explored, as well as inferior petrosal sinus ACTH sampling before and after oCRH. Among the tumor markers examined, elevation of ACTH precursors was uniformly present followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ectopic ACTH tumors are neuroendocrine in nature exhibiting APUD characteristics, their 2 markers, neuron-specific enolase and chromogranins are very useful. The imaging procedures for localization of the tumor ranged from chest X-rays to computed tomography and magnetic resonance of the chest and abdomen. Abdominal ultrasonography was also useful. Finally somatostatin receptor scintigraphy permitted demonstration of unrecognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC processing were evaluated in ectopic tumors and/or metastases. Occult ectopic ACTH syndrome of more than 4-6 months of symptoms without the emergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependent Cushing's disease, inferior petrosal sinus sampling for ACTH after oCRH stimulation established the diagnosis in over 90% of the cases. 60% of the occult tumors were thoracic carcinoids (3/4 bronchial carcinoids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndrome of ectopic CRH syndrome (6 published cases) leading to excessive stimulation of the pituitary which became hyperplastic and secreted excessive amounts of ACTH is discussed. Finally, the 12 published cases and 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and thymic carcinoids.

Mouse excitatory amino acid transporter EAAT2: isolation, characterization, and proximity to neuroexcitability loci on mouse chromosome 2.

Glutamate and aspartate are excitatory neurotransmitters that have been implicated in a number of pathological states of the nervous system. Accumulation of extracellular excitatory amino acids can be cytotoxic and may also lower the seizure threshold in epilepsy. An important function of the Na(+)-dependent high-affinity excitatory amino acid transporter (EAAT) is the reuptake of secreted amino acid neurotransmitter, possibly maintaining extracellular amino acid concentrations at nontoxic and nonepileptogenic levels. We have isolated the mouse cDNA for EAAT2, a neurotransmitter transporter that shares extensive amino acid sequence homology with one of several previously cloned high-affinity glutamate transporters. The mouse EAAT2 amino acid sequence shares 99 and 97% identity with its rat and human homologues, respectively. It is expressed predominantly in the brain, where it may function as a glia-specific transporter. In an interspecific backcross analysis Eaat2 maps to the central region of mouse chromosome 2, where it is located near quantitative trait loci that modulate neuroexcitability and seizure frequency in mouse models of alcohol withdrawal and epilepsy.

The mouse and human excitatory amino acid transporter gene (EAAT1) maps to mouse chromosome 15 and a region of syntenic homology on human chromosome 5.

The gene for human excitatory amino acid transporter (EAAT1) was localized to the distal region of human chromosome 5p13 by in situ hybridization of metaphase chromosome spreads. Interspecific back-cross analysis identified the mouse Eaat1 locus in a region of 5p13 homology on mouse chromosome 15. Markers that are linked with EAAT1 on both human and mouse chromosomes include the receptors for leukemia inhibitory factor, interleukin-7, and prolactin. The Eaat1 locus appears not to be linked to the epilepsy mutant stg locus, which is also on chromosome 15. The EAAT1 locus is located in a region of 5p deletions that have been associated with mental retardation and microcephaly.

Serum testosterone fractions in women: normal and abnormal clinical states.

The potential usefulness of determining serum testosterone (T) fractions in women, ie, sex hormone-binding globulin (SHBG)-bound T, albumin-bound T (Alb-T), and free T (FT) fractions, was explored in a variety of clinical situations. Serum T, SHBG, and albumin concentrations were measured by standardized methods and using binding constants of T to SHBG and albumin, we calculated serum T fractions, which agreed remarkably with measured values of SHBG-T and nonbound T. Serum T levels did not change in normal women examined during the follicular and luteal phases of the menstrual cycle, but SHBG levels were elevated in the luteal phase, changing the distribution of T, with increased SHBG-T and less T distributed to other fractions. Women taking oral contraceptives had decreased serum T levels, but use of androgen-like oral contraceptives decreased SHBG levels and T distribution to this binding protein, whereas use of non-androgen-like oral contraceptives increased SHBG levels, resulting in the expected shift of T fractions. Women receiving phenytoin for seizure disorders and women with Graves' disease exhibited increased SHBG levels with concomitant increased SHBG-T and decreased distribution of T to nonbound fractions. Women with hirsutism exhibited decreased SHBG levels irrespective of total serum T levels, and the T/SHBG ratio was elevated in this population. However, of interest were women with morbid obesity (nonhirsute) who had similar low levels of SHBG and T/SHBG ratios that were indistinguishable from those of hirsute women.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the hypothalamic-pituitary-gonadal axis in men after cadaver kidney transplantation and cyclosporine therapy.

A variety of plasma androgens, estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, cortisol, and thyroid parameters were examined in 10 men followed serially before and after cadaver kidney transplantation. Before transplantation, plasma testosterone levels were below normal in 8 of the 10 men. Free testosterone, follicle-stimulating hormone, and luteinizing hormone were at the lower range of normal values, yet plasma estradiol levels were elevated 3-fold, and prolactin levels were also high. One month after transplantation, all hormones measured were suppressed, probably reflecting high-dose steroids and multiple-drug regimens used in the period following the operation. After 3 months, when other immunosuppressants were reduced and cyclosporine dosage was stabilized, plasma testosterone, androgens, follicle-stimulating hormone, and luteinizing hormone levels were restored toward normal. After 12 months, plasma testosterone levels exceeded pretransplant levels. Plasma estradiol and prolactin levels dramatically decreased after transplantation and remained in the normal range thereafter. These data indicate that abnormalities of plasma estradiol and prolactin levels observed in patients with end-stage renal disease are restored toward normal after cadaver kidney transplantation. Androgen levels that were suppressed in the period immediately after transplantation were restored to normal levels in the succeeding months despite chronic usage of cyclosporine, suggesting that cyclosporine, in currently used doses, does not prevent the restoration of the hypothalamic-pituitary-testicular axis.

Treatment of hirsutism in women with flutamide.

OBJECTIVE: To explore the clinical usefulness of the antiandrogen flutamide in the treatment modality for hirsutism in women. DESIGN: Nine women with hirsutism were assessed before and then monthly for 3 months on a regimen of flutamide 250 mg three times a day as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgenic parameters. SETTING: Patients were followed in the Out-Patient Department of the Hospital das Clinicas, Sao Paulo, Brazil. Hormonal assays were performed in the Hormone Laboratories of Hospital das Clinicas and the Endocrine Research Laboratory at Newark Beth Israel Medical Center, Newark, New Jersey. PATIENTS: Nine women with moderate hirsutism were treated with flutamide. Six women were previously diagnosed as having idiopathic hirsutism, and three women were diagnosed as having polycystic ovary syndrome. INTERVENTION: All women were treated with flutamide 250 mg three times a day for 3 months. MAIN OUTCOME MEASURE: Improvement of hirsutism was assessed using the Ferriman-Gallwey hair density index. Side effects of drug therapy (deterioration of menses and dry skin) were explored. Androgen parameters included testosterone (T), sex hormone-binding globulin, bound, nonbound, and free T, androstanediol glucuronide, and others. RESULTS: After 3 months of flutamide alone, Ferriman-Gallwey scores improved in seven of nine women with mean scores decreasing from 28.1 +/- 0.6 to 24.5 +/- 0.6. None of the androgenic parameters changed during this period of time. Follicle-stimulating hormone and luteinizing hormone response to gonadotropin-releasing hormone was unchanged after flutamide. CONCLUSION: Flutamide favorably influenced hirsutism in women, with differences noted after only 3 months of therapy. More prolonged and detailed studies of this drug as the sole therapeutic agent for treatment of hirsutism seems warranted.

Sex hormone metabolism in upper and lower body obesity.

Morbid obesity has been previously shown to be associated with excessive production and metabolism of a variety of androgens and estrogens. Further, SHBG is lowered, resulting in high levels of 'free' testosterone. We have re-examined these parameters in morbidly obese women with upper vs lower body adipose distribution. Upper body obesity was associated with greater increases in production and clearance of testosterone and dihydrotestosterone compared to lower body obesity. Further, SHBG levels were lower resulting in high serum levels of free T and free E2 in this obesity phenotype. By contrast, lower body obesity was associated with increased peripheral aromatization of androstenedione resulting in higher urinary E1 production rates. The biologic significance of these hormonal differences in obesity phenotypes as well as the potential role of the androgen-estrogen environment in determining body fat distribution is considered.

Responsible weight loss in New Jersey.

Very low-calorie formula diets (VLCDs) are an accepted method of achieving safe and effective weight loss for the morbidly obese. Under supervised medical surveillance and with a support team of dietitians and patient counsellors, weight loss of 40 or more pounds is achieved in 80 percent of patients. The authors present guidelines for assessing responsible weight loss programs along with a list of programs available in New Jersey.

Androgen-estrogen metabolism in women with upper body versus lower body obesity.

Androgen and estrogen production rates were examined in 29 morbidly obese women with upper or lower body obesity. Although blood production rates of testosterone (T), dihydrotestosterone, and androstenedione (A4) were elevated in all of these women, those with upper body obesity (waist-height ratios, greater than 0.85) had higher T and production rates than women with lower body obesity (waist-height ratio less than 0.75). A4 was equally elevated in women with upper and lower body obesity. Peripheral aromatization of A4 to estrone (E1) averaged 1.67% in women with upper body obesity, but was elevated at 2.54% in women with lower body obesity. Urinary E1 production rates averaged 466 +/- 295 nmol/day (172 +/- 109 micrograms/day) in women with upper body obesity. Thus, women with lower body obesity had higher E1 production rates due entirely to increased peripheral aromatization. Women with upper body obesity were observed to have higher serum T and estradiol (E2) levels than women with lower body obesity. Further, upper body obesity was associated with decreased levels of sex hormone-binding globulin (16.1 +/- 5.7 nmol/L vs. 18.9 +/- 6.1 in women with lower body obesity). As a result, free T levels averaged 98.8 +/- 39.2 pmol/L in women with upper body obesity vs. 82.2 +/- 33 in women with lower body obesity. Similarly, serum free E2 levels were higher in women with upper body vs. lower body obesity. The data demonstrate that sex hormone production and metabolism are different in morbidly obese women with these differing phenotypes. Women with upper body obesity have higher androgen production rates and higher free T and free E2 levels, whereas women with lower body obesity make increased amounts of E1 from peripheral aromatization. The biological significance of increased aromatization may be offset by increased free E2 levels in women with upper body obesity.

Monthly cyproterone acetate in the treatment of hirsute women: clinical and laboratory effects.

Cyproterone acetate given as a single intramuscular dose of 300 mg monthly for 6 months resulted in significant reduction of hirsutism without appreciable side effects. This regimen resulted in decreased levels of luteinizing hormone (LH) and estradiol in the eight women studied. No significant changes were observed in total serum testosterone (T) levels, however, there was a reduction in sex hormone binding globulin (SHBG), resulting in lowered SHBG-bound T, and an increase in non-SHBG-T over this time. Serum androstanediol glucuronide levels decreased in three of four women, although not to normal levels.

Decreased 3 alpha-androstanediol glucuronide levels in plasma and random urines in male pseudohermaphroditism caused by 5 alpha-reductase deficiency.

Concentrations of 3 alpha-diol glucuronide (3 alpha-diol G) in plasma and/or random urine samples were determined in seven subjects with familial male pseudohermaphroditism (FMP) due to 5 alpha-reductase deficiency (5 alpha-RD). All subjects were natives of an isolated Turkish village with a high incidence of consanguineous marriage. A specific and sensitive antibody to 3 alpha-diol was used for radioimmunoassay of 3 alpha-diol G after hydrolysis and chromatographic purification. The mean plasma 3 alpha-diol G in three subjects (31 ng/dL) was much lower than the normal male concentration (516 +/- 50) (+/- SE) and was even lower than normal female values (119 +/- 10.9 ng/dL). In five subjects, mean urinary 3 alpha-diol G in random urine samples was 7.6 (range 2.1 to 12.7) ng/mg creatinine. This was considerably decreased compared with the mean adult male concentration of 65.4 +/- 9.4 and even lower than normal age-matched nonhirsute female values (19.6 +/- 2.1 ng/mg Cr). To validate the use of 3 alpha-diol G/creatinine ratios in random urine samples, correlations of three consecutive eight-hour samples with 24-hour values were determined in 8 male and 3 female age-matched controls. There was an excellent correlation (r = .95) and the linear regression line (y = 0.51x + 2.58) indicates that the 24-hour excretion of 3 alpha-diol G in microgram/24 h is approximately twice the random urinary concentration in ng/mg Cr.(ABSTRACT TRUNCATED AT 250 WORDS)

Free testosterone levels during the menstrual cycle in obese versus normal women.

In a group of seven normally ovulating moderately obese women, testosterone parameters were studied throughout the menstrual cycle and compared with values obtained in normal-weight control women. Plasma T, percent free T (unbound), and free T concentrations were higher and exhibited little variation during the phases of the cycle compared with the normal-weight controls. Testosterone production and its parameters thus are higher in even moderately obese women.

Medical adrenalectomy for advanced prostatic cancer: clinical and hormonal effects.

We examined the effect of medical adrenalectomy on the clinical and hormonal responses in 50 men with disseminated prostatic carcinoma. Patients refractory to initial hormonal therapy were treated with aminoglutethimide and hydrocortisone (AG-HC) and evaluated by the criteria of the National Prostatic Cancer Project. Eight patients showed a partial response (PR), and 17 remained stable while receiving these medications. Survival times for these two groups averaged 87.8 and 38 weeks, respectively. In contrast, 17 men were unresponsive to this therapy, exhibiting progressive disease with a mean survival time of 18 weeks. Eight patients could not tolerate the drug regimen or were lost to follow-up. Serum and urinary hormone profiles determined serially during AG-HC therapy revealed that all measured serum androgens and estrogens were significantly lowered by AG-HC treatment; however, specific hormones, including free testosterone, dihydrotestosterone, estrone, and estradiol were suppressed to a greater degree in responders (R) as compared with nonresponders (NR). Urinary excretion of 17-ketosteroids did not change during AG-HC therapy, but specific androgen metabolites, including testosterone glucuronide and androstanediol glucuronide, were suppressed by 50% during AG-HC therapy. We showed modest clinical benefit of AG-HC therapy in advanced prostatic cancer. That greater hormonal suppression was associated with greater responsiveness to this therapy raises the hope that further manipulations directed against suppression of extratesticular androgens may be a useful approach as second-line treatment of advanced prostatic cancer.

An eight-year experience with a very-low-calorie formula diet for control of major obesity.

We have utilized a very-low-calorie formula diet (VLCD) along with multidisciplinary group counselling in an attempt to achieve and maintain major weight loss in 4026 morbidity obese patients. Using a 420-cal protein supplement (Optifast), men lost weight, at an average of 4.6 +/- 0.9 lb/week and women, 3.1 +/- 1.1 lb/week. Men remained on the VLCD an average of 13.2 weeks, resulting in a mean weight loss of 66.0 +/- 8.1 lb; women remained on the fast an average of 14.1 weeks, with an average loss of 47.3 +/- 4.2 lb. Outcome analysis revealed that 25 percent of patients were unable to adapt to this approach, dropping out within the first 3 weeks. Of the patients remaining in the program, 68 percent lost considerable weight, but did not reach their goal; of this group, recidivism was extremely high, with only 5-10 percent maintaining weight loss after 18 months. Thirty-two percent of the patients successfully attained goal weight; the holding rate of this group has been considerably greater, with 30 percent of women and 58 percent of men maintaining weight loss (within 10 lbs) for a minimum of 18 months. Complications of obesity i.e. hypertension, type II diabetes mellitus, and hyperlipidemias were remarkably improved after weight loss. Complications of the VLCD including cardiac abnormalities, were minimal. Our 8-year experience strongly suggests that the VLCD approach using high quality protein supplement and multi-disciplinary counselling provides a reasonable success rate for achieving and maintaining weight loss in the morbidity obese population.

The source(s) of estrogen production in hirsute women with polycystic ovarian disease as determined by simultaneous adrenal and ovarian venous catheterization.

To determine the significant source(s) of estrogen production in women with polycystic ovarian disease (POD), 12 women underwent selective adrenal and ovarian vein catheterization, with simultaneous peripheral blood samplings for determination of cortisol, androstenedione (delta 4A), testosterone, estrone (E1), and estradiol (E2). Ovarian vein E2 gradients were observed in 11 of the 12 patients with a mean of 13.4, whereas adrenal blood samples did not demonstrate significant E2 gradients. Seven of 8 patients exhibited ovarian secretion of E1, with a mean gradient of 13.6 times that of peripheral blood, whereas 4 of the 8 adrenal samples showed E1 gradients. The mean value was 1.4 times peripheral levels. No significant correlations were found between peripheral E1 levels and body weight or degree of adiposity, nor was there a relationship between obesity and E1/delta 4A molar ratio in peripheral blood. The subjects with the highest ovarian delta 4A levels had a significant correlation between peripheral delta 4A and E1. Therefore, our data indicate a significant contribution of ovarian E1 secretion to the peripheral E1 pool in addition to the extraglandular conversion of delta 4A to E1. There was general lack of correlation between peripheral E1 concentrations and plasma E2, and these relationships versus body size suggest that the major source of E2 in women with POD was ovarian secretion.

Clinical usefulness of plasma androstanediol glucuronide measurements in women with idiopathic hirsutism.

Serum androstanediol glucuronide (3 alpha-diol G), a metabolite of the active androgens dihydrotestosterone and androstanediol, was elevated in 28 consecutive women with idiopathic hirsutism (IH). The mean 3 alpha-diol G level in the women with IH was 487 +/- 192 (+/- SD) ng/dL compared to 119 +/- 37 ng/dL in normal women (n = 50), and only 1 patient had a value overlapping with the normal range. Since 3 alpha-diol G appears to be formed entirely in target organs and has a long serum half-life, we studied its clinical usefulness by following women with IH during treatment. In 15 of 17 women with IH treated for 1-4 yr with glucocorticoids, contraceptives, or spironolactone, serum 3 alpha-diol G levels changed concordantly with clinical responses, in contrast to the poor concordance of serum testosterone (5 of 17), free testosterone (7 of 17), and androstenedione (7 of 17). Specifically, in IH patients treated with spironolactone, serum testosterone, free testosterone, and androstenedione levels changed little, yet clinical improvement frequently occurred, and this improvement was reflected by concomitantly lowered 3 alpha-diol G levels. Further, in 4 IH patients, discontinuation of effective therapy resulted in prompt increases in serum 3 alpha-diol G as harbingers of worsening hair growth. We, thus, conclude that serum 3 alpha-diol G measurements are clinically useful in evaluating hirsute women and correlate with the clinical responses to therapy.