Clinical effectiveness of a new oral curcumin formulation in acute non-infectious uveitic macular edema: a 12-month observational study.

OBJECTIVE: Oral supplementation with curcumin demonstrated a beneficial effect on some ocular diseases, including uveitis and macular edema. This study aimed to evaluate the effectiveness and safety of a curcumin formulation with the hydrophilic carrier (CHC; Diabec®, Alfa Intes, Italy) as an adjuvant to standard steroid treatment in adults suffering from acute non-infectious uveitic macular edema (NIUME). PATIENTS AND METHODS: This was a monocenter prospective observational study carried out between January 2019 and May 2020 on consecutive patients with a new diagnosis of NIUME. Patients were treated with standard therapy or with a CHC add-on to standard treatment. The observation period for each patient was 12 months. The Best Corrected Visual Acuity (BCVA) and the Central Macular Thickness (CMT) were the primary outcomes; Foveal Avascular Zone (FAZ) and intraocular pressure (IOP) were also assessed, along with safety data. RESULTS: A total of 43 eyes of 26 patients were analyzed. CHC-treated eyes showed an improvement in mean BCVA from baseline (0.34 logMar) to T6 (0.20 logMar) and T12 (0.19 logMar; p≤0.05 and p≤0.01, respectively); CMT decreased from a mean of 320 µm (T0) to 278 µm (T6; p≤0.05) and 272 µm (T12; p≤0.01). A significant improvement of mean BCVA in the CHC group at T6 and T12 was reported compared to the control group (p≤0.01). FAZ and IOP showed no statistically significant variations in both groups. No adverse events were recorded. CONCLUSIONS: CHC as an adjuvant treatment improved the anatomical and functional outcomes, without significant side effects in eyes affected by the recent onset of NIUME, compared to the sole standard therapy.

Sunitinib: bridging present and future cancer treatment.

Tyrosine kinase receptors (RTKs) are a heterogeneous group of transmembrane proteins involved in signal transduction. These receptors are expressed in many different cells and regulate cellular growth, differentiation and angiogenesis. Overexpression and/or the structural alteration of different RTKs classes are generally associated to cancer and, when RTKs-mediated signal transduction pathways are abnormally activated, generate cancer growth, angiogenesis and metastatization. Therapeutic intervention targeting RTKs concerns antagonist drugs as little molecules or monoclonal antibodies. Sunitinib malate is a little molecule able to block intracellular tyrosine kinase domain of RTKs, which has both direct anticancer and antiangiogenetic activity. Sunitinib targets selectively vascular endothelial growth factor, KIT, Flt3 and platelet-derived growth factor receptors and the receptor encoded by the ret proto-oncogene. This drug is used in the treatment of gastrointestinal stromal cancer (GIST) resistant to imatinib and metastatic renal cell carcinoma (RCC). In this review, we report preclinical data of sunitinib, even about synergism with chemotherapy and radiotherapy, data relative to phase III trials of sunitinib in the treatment of GIST and RCC, and we try to plan what will be future applications of sunitinib in different types of cancer, even in association to chemotherapy, radiotherapy and monoclonal antibodies.

Growth hormone secretion in polytransfused prepubertal patients with homozygous beta-thalassemia. Effect of long-term recombinant GH (recGH) therapy.

Growth was monitored in 133 male and 150 female North Sardinian prepubertal patients with homozygous beta-thalassemia in order to ascertain the incidence of GH deficiency (GHD) and the effects of long-term recombinant GH (recGH) treatment on growth velocity and bone maturation. A significant reduction in growth velocity and a fall in IGF-I levels was observed in 19 male and 16 female patients (12.3%). Their peak GH responses to GHRH (5.45+/-0.78 and 4.99+/-0.86 ng/ml) and clonidine administration (4.21+/-0.32 and 4.15+/-0.27 ng/ml in males and females, respectively) were markedly reduced with respect to control subjects (p<0.01). No statistically significant correlation was found between chronological age, number of blood units received, plasma ferritin levels and plasma IGF-I levels as well as with peak GH response to stimulation. Thalassemic patients with GHD had plasma ferritin levels (1382.44+/-160.34 and 1255.23+/-139.81 ng/ml in males and females, respectively) significantly lower than those recorded in the other patients (2848.94+/-283.61 and 3077.82+/-220.51 ng/ml). Patients with GHD were treated with recGH for an average period of 59 months (range 26-124). Treatment was able to restore growth and to increase significantly plasma IGF-I levels. Growth velocity at the end of the first yr of treatment was 6.78+/-1.21 and 6.11+/-0.85 cm/yr in males and females, respectively. Growth velocity values and plasma IGF-I levels remained significantly higher than basal values throughout the period of treatment. However, treatment was unable to normalize bone maturation since bone age values were always reduced with respect to chronological age. No incidence of side effects was observed. These data indicate that GHD, when present, is one but not the sole cause of delayed bone maturation and height deficiency in thalassemia.

Evaluation of serum leptin levels and thyroid function in morbidly obese patients treated with bariatric surgery.

Biliopancreatic diversion (BPD), a gastrectomy with a long ROUX en Y reconstruction, reduces intestinal absorption by delaying the mixing of food and biliopancreatic juices, and induces persistent weight loss in obese patients unresponsive to medical treatments. The levels of leptin (a plasma protein synthesised in human adipose tissue) are increased in obese subjects and significantly decrease after a major weight loss. A possible role of thyroid hormones in regulating adipose tissue metabolism in humans has been proposed, but it is not universally accepted and the relationship between thyroid function and leptin levels has not yet been clearly defined. We studied serum leptin, TSH, fT4 and fT3 levels in 38 obese patients (26 women and 12 men), before and 12 months after BPD. There was a significant post-surgical decrease in BMI and circulating leptin levels in all of the treated subjects, but thyroid function did not seem to be affected (TSH and fT4 levels were unchanged). However, fT3 levels significantly decreased after surgery. Our data suggest that BPD-induced malabsorption has no direct effect on thyroid function, but possibly reduces the peripheral conversion of thyroxine to T3. Further studies seem to be necessary to clarify the clinical relevance of these observations.

Effects of 12 months rec-GH therapy on bone and collagen turnover and bone mineral density in GH deficient children with thalassaemia major.

Children suffering from thalassaemia major are reported to have growth delay and bone alterations even when well transfused and chelated. In the present study we evaluated bone and collagen turnover (bone Gla-protein, BGP; carboxyterminal telopeptide of type I collagen, ICTP; aminoterminal propeptide of type III procollagen, PIIINP, respectively) and bone mineral density (BMD) in 5 pre-pubertal GH deficient thalassaemic children before and during rec-GH treatment (0.6 IU/kg/week). Data were compared with those recorded in an age- and sex-matched control group. Before treatment, serum BGP and ICTP levels were significantly lower (p<0.0001) in children with thalassaemia (9.3+/-0.7 ng/ml and 5.3+/-0.5 ng/ml, respectively) than in healthy controls (18.9+/-0.9 ng/ml and 14.4+/-0.6 ng/ml, respectively), while serum PIIINP levels did not significantly differ in the two groups (6.7+/-0.7 ng/ml vs 6.7+/-0.7 ng/ml). Mean lumbar BMD values of patients (0.62+/-0.05 g/cm2) were significantly lower (p<0.05) than those recorded in healthy controls (0.78+/-0.01 g/cm2), while femoral BMD values were similar in the two groups (patients: 0.70+/-0.08 g/cm2 vs controls: 0.74+/-0.01 g/cm2). One-year GH therapy significantly increased height velocity (from 2.3+/-0.2 cm/year to 6.1+/-0.4 cm/yr, p<0.0001) and IGF-I levels (from 61.6+/-15.4 to 342+/-38.5 ng/ml, p<0.005). Serum BGP (basal: 9.3+/-0.7 ng/ml, 6th month: 10.8+/-0.6 ng/ml, 12th month: 14.9+/-1.4 ng/ml), ICTP (basal: 5.3+/-0.5 ng/ml, 6th month: 7.9+/-0.8 ng/ml, 12th month: 10.9+/-1.7 ng/ml) and PIIINP levels (basal: 6.7+/-0.7 ng/ml, 6th month: 9.9+/-1.0 ng/ml, 12th month: 9.6+/-1.4 ng/ml) significantly increased (p<0.05), while no significant effects were observed on lumbar and femoral BMD values. Although the GH-induced stimulation of bone turnover markedly increased BGP (+60%) and ICTP (+105%) levels, one-year GH therapy was not sufficient to completely normalize these parameters, which remained significantly lower than in healthy controls. In conclusion, our study shows that pre-pubertal GH deficient children with thalassaemia major have reduced bone turnover (both bone formation and resorption) and lumbar BMD values, thus indicating that bone metabolism should be monitored and improved even in well-transfused patients. One-year GH treatment is able to increase, but not normalize, bone turnover, this effect being insufficient to improve BMD values. More prolonged periods of GH therapy are probably requested to positively affect both bone turnover and BMD values in GH deficient thalassaemic patients, as occurs in children and adults with GH deficiency.

Use of testosterone to prevent cyclophosphamide-induced azoospermia.

BACKGROUND: Prepubertal patients receiving chemotherapy are relatively resistant to cyclophosphamide-induced germinal cell alterations. OBJECTIVE: To study the possible protective effect of testosterone used to inhibit germinal cell activity in men who are receiving cyclophosphamide. DESIGN: Randomized, clinical trial. SETTING: University medical center. PATIENTS: 15 patients with the nephrotic syndrome who were treated with cyclophosphamide for 6 to 8 months. INTERVENTION: Five patients received daily oral cyclophosphamide, five received cyclophosphamide in monthly bolus injections, and five received monthly intravenous boluses of cyclophosphamide plus testosterone (100 mg intramuscularly every 15 days). MEASUREMENTS: Sperm counts, serum follicle-stimulating hormone levels, and serum luteinizing hormone levels were measured before, during, and after treatment with cyclophosphamide alone or cyclophosphamide plus testosterone. RESULTS: The 10 patients who did not receive testosterone became azoospermic during cyclophosphamide therapy. In only 1 of the 10 patients did the sperm count return to normal 6 months after discontinuation of therapy. Follicle-stimulating hormone levels were elevated in these patients (mean +/- SE, 19.20 +/- 1.28 IU/L in patients receiving oral cyclophosphamide and 16.04 +/- 2.22 IU/L in patients receiving intravenous cyclophosphamide alone). All 5 patients who received testosterone became azoospermic or severely oligospermic during treatment but had a normal sperm count 6 months after the discontinuation of therapy. In these patients, the mean sperm count was 45.78 +/- 3.89 x 10(6)/mL and follicle-stimulating hormone levels were normal (5.08 +/- 0.56 IU/L). CONCLUSION: Testosterone given to men before and during an 8-month cycle of cyclophosphamide therapy for the nephrotic syndrome may preserve fertility.

Parathyroid function and bone metabolism in children with beta thalassaemia major: effects of sex steroid treatment.

OBJECTIVE: Data on parathyroid function in patients with homozygous beta-thalassaemia are discordant. Moreover, there is no report on the effects of sexual steroid treatment on bone metabolism in these patients. METHODS: Serum parathyroid hormone (PTH), calcitonin (CT) and osteocalcin (GLA protein) levels were measured in 121 patients. Thirty-three prepubertal subjects were treated for six months with sexual steroids. RESULTS AND CONCLUSIONS: Primary hypoparathyroidism was present in 3.3% of the patients. Osteocalcin levels were found to be lower in thalassaemic subjects than in controls, whereas CT values were similar. No effects of sexual steroid administration on plasmatic levels of osteocalcin were observed.

Chronic treatment with parlodel LAR of patients with prolactin-secreting tumours. Different responsiveness of micro- and macroprolactinomas.

UNLABELLED: Forty-one patients with prolactinoma (25 micro-, 16 macroprolactinomas) were treated with a long-acting injectable preparation of bromocriptine (Parlodel LAR, Sandoz), 25-100 mg (mostly 50 mg) in every 4-8 weeks for as long as 43 months (median 19 months). The first injection caused a prompt fall of plasma PRL which reached its nadir value after 3 days. Thereafter, hormone levels remained well below initial values for 4 weeks or longer, though with the tendency, more pronounced in microprolactinoma patients, to rise again toward baseline. The prevalence of PRL normalization was greater in the macro- than in the microprolactinoma group. By repeated injections plasma PRL could be kept close to or within the normal limits in most of the patients. However, the extent of PRL inhibition was significantly greater in macro- than in microprolactinoma patients (p less than 0.01). Clinical improvement occurred in the majority of the patients, shrinkage of the tumour in 50% of them. Adverse reactions were generally mild or of moderate severity and subsided spontaneously in 24 h. They were less frequent (NS) and less severe (p less than 0.05) in macro- than in microprolactinoma patients. IN CONCLUSION: a. injectable bromocriptine (Parlodel LAR) is a highly effective preparation particularly suitable for the long-term treatment of tumourous hyperprolactinemia; b. patients with macroprolactinoma exhibit, compared with microprolactinoma patients, better responsiveness and better tolerability to injectable bromocriptine.

Treatment with biosynthetic growth hormone of short thalassaemic patients with impaired growth hormone secretion.

OBJECTIVE: Impairment of linear growth is a common clinical feature in patients with beta-thalassaemia major. Although growth hormone secretion appears to be normal in many short thalassaemic patients, it proves to be deficient in some of them. In these cases, administration of biosynthetic growth hormone seems justified. The aim of this study was to evaluate the effect of such treatment in a group of patients with beta-thalassaemia major presenting with growth failure and impairment of growth hormone secretion. DESIGN: Recombinant human growth hormone, 0.6 U/kg body weight per week, given subcutaneously in three divided doses, was administered for 12 months. PATIENTS: Eight prepubertal patients with beta-thalassaemia major, presenting with severe growth retardation and impaired growth hormone secretion in response to provocative stimuli (insulin-induced hypoglycaemia, L-dopa and growth hormone-releasing hormone), were investigated. MEASUREMENTS: Height and pubertal stage of the patients, as well as plasma levels of insulin-like growth factor I, were determined before, during and after biosynthetic growth hormone treatment. RESULTS: During the first 6 months of therapy, a significant increase of growth velocity was observed, from a mean pretreatment value of 2.1 +/- 0.45 cm/year to a value of 4.8 +/- 0.66 cm/year (P less than 0.002). Mean growth rate at 12 months (4.1 +/- 0.50 cm/year), though slightly decreased in comparison to that recorded at 6 months, was still significantly higher than basal (P less than 0.001). A significant increase in plasma levels of insulin-like growth factor I was recorded during treatment (2.82 +/- 0.47 vs 0.96 +/- 0.22 U/ml, P less than 0.005). No side-effects, adverse reactions or alterations in routine laboratory examinations ensued during or after therapy. CONCLUSIONS: It appears from these data that biosynthetic growth hormone administration is worth serious consideration in patients with beta-thalassaemia major presenting growth retardation and impaired growth hormone secretion.

Effect of angiotensin converting enzyme inhibition on the menstrual cycle of hypertensive women.

Angiotensin II was reported to play a key role in ovulation in rats and it seems also to be involved in the regulation of LH release. Thus, we studied the effect of chronic ACE inhibition on the menstrual cycle, measuring daily plasma estradiol, progesterone, LH and FSH, and renin and prorenin before and during the third month of treatment with enalapril (10 mg b.i.d.) in 10 mild essential hypertensive women. Blood pressure was normalized by treatment. The cyclical changes of steroids and gonadotrophins were unaffected in their temporal relationships and in the magnitude of their variation during the experimental cycle compared with the basal cycle. A synchronization of plasma prorenin with the other hormones was seen both before, as previously reported, and during enalapril treatment. Our data show that peripheral blockade of angiotensin I conversion does not affect the pituitary guidance of the ovarian hormonal response or the ovarian prorenin release during the menstrual cycle. Our data are in agreement with the hypothesis that circulating angiotensin II does not play a key role in the human fertility process and that hydrophilic ACE inhibitors can be safely used in the treatment of hypertensive women of reproductive age.

Comparison between a slow-release oral preparation of bromocriptine and regular bromocriptine in patients with hyperprolactinemia: a double blind, double dummy study.

The efficacy and tolerability of a slow-release preparation of bromocriptine (Parlodel SRO) were compared to those of conventional bromocriptine (Parlodel R) in a double blind, double dummy study of 12 hyperprolactinemic women (plasma PRL 81.3 +/- 4.73, ng/ml mean +/- SEM). For 2 weeks, the patients received 2.5 mg b.i.d. Parlodel R or 5 mg once daily Parlodel SRO; for the following 2 weeks, the dose of the drugs was doubled. The patients were then treated, in an open study, with 2.5-10 mg daily Parlodel SRO for 6 months. Both preparations caused a prompt and sharp PRL fall. Hormone levels remained inhibited over the whole month of observation with both preparations. Daily PRL profiles were very close with either drug although morning PRl levels were slightly higher during Parlodel SRO than during Parlodel R administration. Doubling the doses of the two drugs did not result in further significant lowering of PRL values. During the 6-month study with Parlodel SRO, plasma PRL further decreased and normalized in 11 of 12 patients. Clinical improvement occurred in the majority of cases. Tolerability of Parlodel SRO appeared to be better, though without statistically significant differences, than that of Parlodel R. Side effects were less important with the former compound in their number, severity and duration. In conclusion, thanks to its favourable pharmacological profile, Parlodel SRO appears to be a valuable alternative to regular bromocriptine in the management of hyperprolactinemia.

Circulating prorenin and renin in response to intravenous adrenocorticotrophic hormone in essential hypertension.

Plasma prorenin and renin changes after a bolus injection of 25 U intravenous adrenocorticotrophic hormone (ACTH, synacthen) were studied in seven untreated uncomplicated essential hypertensives over a period of 24 h. Plasma prorenin did not change significantly during the study, whereas renin after 24 h was higher than at baseline (4.3 +/- 0.6 versus 2.3 +/- 0.9 ng angiotensin I (Ang I)/ml per h, P less than 0.01). We conclude that endogenous glucocorticoid stimulation induced by exogenous ACTH and ACTH itself seem to induce a secondary or tertiary rather than a primary effect on the human renin gene.

Evaluation of anterior pituitary function in hypertensive patients following inhibition of angiotensin II generation.

The Authors investigated anterior pituitary function in hypertensive patients in basal conditions and following a 15-day course of treatment with captopril, a drug which blocks the generation of Angiotensin II (Angio II). No differences were observed for any of the pituitary hormones except ACTH, whose response to hypoglycemia was significantly blunted by the pharmacological treatment. A possible role of Angio. II in modulating some aspects of pituitary function is proposed.

Angiotensin converting enzyme inhibition reduces ACTH release due to hypoglycaemia.

To investigate the role of Angiotensin II in the release of ACTH, the response of adrenocorticotrophic hormone to hypoglycaemia was studied before and during treatment with an angiotensin converting enzyme inhibitor, enalapril, in 15 male patients with essential hypertension. Plasma levels of ACTH were measured before and 60, 90 and 120 min after an i.v. bolus of normal saline, as placebo, and, 3 days later, after an i.v. bolus of regular insulin (0.15 U/Kg b.w.). Enalapril treatment was then started and both placebo and hypoglycaemic tests were repeated 15 days thereafter. No changes in ACTH plasma levels were observed after acute normal saline either before or during enalapril treatment. On the contrary, hypoglycaemia induced a sharp increase of ACTH before enalapril (from 19.5 +/- 4.1 to 74.4 +/- 13.0 pg/ml, p less than 0.01 60 min after insulin) but not during ACE inhibition (from 26.1 +/- 6.2 to 34.6 +/- 5.9 pg/ml, NS, at min 60 of the study). The present data confirm our previous observation on the reduction of the hypoglycaemic-induced ACTH release during ACE inhibition with captopril and support the hypothesis that circulating Ang II may exert a facilitating role on adrenocorticotrophic hormone release.

Blunted adrenocorticotrophic hormone release during captopril treatment.

High tissue levels of angiotensin II have been reported in the median eminence suggesting a possible role in the regulation of adrenocorticotrophic hormone (ACTH) secretion. To verify this hypothesis in man, the pituitary-adrenal axis response to hypoglycaemia was studied before and during captopril treatment in eight male essential hypertensive patients (stage I WHO; aged 35-52 years). Plasma levels of ACTH, cortisol and glucose were measured before and 60, 90 and 120 min after an intravenous bolus of normal saline as placebo an, 3 days later, after an intravenous bolus of rapidly acting insulin (0.1 IU/kg body weight). Captopril treatment was then started and both placebo and hypoglycaemic tests were repeated 15 days thereafter. No changes in ACTH, cortisol or glucose plasma levels were observed after acute normal saline, either before or during captopril administration. On the contrary, hypoglycaemia induced a sharp increase of ACTH plasma before captopril (from 27.7 +/- 11 to 131.30 +/- 26 pg/ml, P less than 0.01, 60 min after insulin) but not during angiotensin converting enzyme (ACE) inhibition (from 28.9 +/- 9 to 42.9 +/- 11 pg/ml, NS, at min 60 of the study). Our present data, showing a blunted ACTH response to hypoglycaemia during ACE inhibition, suggest that circulating angiotensin II may participate in the regulation of the release of the ACTH, possibly by a stimulation of angiotensin II receptors localized in the brain but outside the blood-brain barrier.

Effect of clonidine on stress-induced cortisol release in man during surgery.

The effect of clonidine on stress-induced cortisol secretion was studied in 10 patients undergoing general anesthesia for surgery; six other patients served as a control group and none of them was given clonidine. Central and peripheral alpha 2 stimulation by clonidine (average dose:0.45 mg over 60 minutes) was able to completely suppress cortisol release during surgery.

Failure of nomifensine to reduce serum prolactin levels in patients with hepatic encephalopathy.

In order to investigate whether the variations in prolactin (PRL) secretion found in patients with liver cirrhosis are related to the derangement of neurotransmitter metabolism, serum PRL levels were measured in 8 patients with hepatic encephalopathy (a condition where neurotransmission is severely deranged), in 10 patients with liver cirrhosis but without encephalopathy and in 10 control subjects under control conditions and in response to nomifensine, levodopa and synthetic TRH administration. Inhibition of endogenous catecholamine reuptake by nomifensine was able to significantly reduce PRL levels in normal subjects and in patients with liver cirrhosis, whereas only one out of 8 patients with hepatic encephalopathy showed a reduction in PRL levels. On the contrary, levodopa administration was able to reduce PRL secretion in all the subjects studied. PRL release by TRH was greater in patients with liver disease than in controls. The results seem to indicate that the derangement in neurotransmitter metabolism which occurs in liver cirrhosis is one, but not the sole cause of alterations of PRL secretion in liver cirrhosis. The failure of nomifensine to depress PRL is an early finding in the course of encephalopathy and may be of diagnostic value.

Endocrine functioning in multitransfused prepubertal patients with homozygous beta-thalassemia.

Endocrine function was evaluated in 20 prepubertal patients with homozygous beta-thalassemia treated with frequent transfusions and long term iron chelation therapy. FSH, LH, PRL, and TSH secretion were evaluated by LRH and TRH testing and L-dopa and ACTH were used to assess GH and adrenocortical reserve. No statistically significant differences were found between FSH, LH, PRL, GH, and cortisol secretion in the patients and in normal subjects. There was a relatively high incidence (35%) of primary thyroid impairment since 1 patient had primary hypothyroidism and 6 others had evidence of subclinical hypothyroidism as manifested by increased TSH responses to TRH. However, no statistically significant correlations were found between either serum ferritin levels, total blood transfusions received, and thyroid function.

Suppression of electroacupuncture(EA)-induced beta-endorphin and ACTH release by hydrocortisone in man. Absence of effects on EA-induced anaesthesia.

Auricular electroacupuncture (EA) increased plasma ACTH and beta-endorphin levels significantly in 10 patients receiving EA as an analgesic aid during surgery. Pre-treatment with iv hydrocortisone (200 mg) completely suppressed both ACTH and beta-endorphin release in response to EA without significantly affecting EA anaesthesia in 6 other patients and in a patient with Addison's disease.

A solid phase chemiluminescent immunoassay (LIA) for testosterone glicuronide in diluted urines.

A chemiluminescent immunoassay (LIA) method in solid phase for the measurement of testosterone 17 beta-D-glicuronide (TG) in diluted urine is described, which utilizes as tracer a TG-isoluminol conjugate (TG-ABEI). An IgG fraction of antiserum of TG-BSA, has been passively adsorbed to the walls of polystyrene tubes. After the binding reaction the coated tubes were washed with buffer and the measure of chemiluminescence reaction was performed at high pH. The assay was validated in terms of specificity, accuracy, sensitivity and precision. The values obtained by chemiluminescence immunoassay were compared with that obtained by the RIA method, and the two methods agreed well (r = 0.95, n = 28). The assay method offers the advantage of speed and does not involve the use of radioisotopes or of a centrifugation step. Preliminary results show that the mean 24 h urinary TG excretion in a group of hirsute women is higher than in the control group, and decreases after suppression with dexamethasone for 1 month of therapy.