Dex Therapy Research Articles

Immunopharmacology of cancer vaccines: Restoration of NKG2D levels and functions in metastatic melanoma treated with exosomes

2554 Background: The C-type lectin-like stimulatory immune receptor Natural Killer group 2 receptor (NKG2D) is expressed by NK and CD8+ T cells. NKG2D engagement is a natural mediator of immunosurveillance which can be compromised by locally sustained ligand expression. In cancer patients with NKG2D ligand- expressing tumors, NK and CD8+ T cells often express low levels of NKG2D and are functionally compromised. Dentritic cell-derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection in mice. Two Dex Phase I trials highlighted the and the safety of exosome administration. The observation of clinical regressions in the absence of detectable T cell responses prompted the search for alternate effector mechanisms. We study NKG2D expression and NK cells function in peripheral lymphocytes before and after Dex therapy. Methods: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients were enrolled and received exosome vaccinations. NK cells functions prior or following exosome vaccines were tested in standard Na251CrO4 chromium release assays. NKG2D and NKG2D ligand expression were studied using flow cytometry and/or western blot experiments. Results: In sharp contrast with DC, Dex bear functional NKG2D ligands leading to a selective downregulation of NKG2D activating receptors on autologous NK cells in vitro. Long term administration of Dex could enhance NKG2D expression levels on NK and CD8+ T cells in 50% of patients, restoring killing of NKG2D ligand expressing K562 and autologous tumour. In contrast to NKG2D ligands shed by tumors mediating immunosuppressive activity, exosomal NKG2D ligands promote NKG2D-dependent effector functions in vivo, that might account for the non MHC restricted-antitumor effects observed in the trial. Conclusions: NK cell activation represent a new pharmacodynamic for Dex leading to tumor recognition and regression in vivo. The Phase II trial using Dex shall include the monitoring of NKG2D ligands on Dex preparation and follow up NKG2D levels, functions and polymorphism in patients. No significant financial relationships to disclose.

Dexosomes as a therapeutic cancer vaccine: From bench to bedside

Exosomes released from dendritic cells, now referred as dexosomes, have recently been extensively characterized. Preclinical studies in mice have shown that, when properly loaded with tumor antigens, dexosomes can elicit a strong antitumor activity. Before dexosomes could be used in humans as a therapeutic vaccine, extensive development work had to be performed to meet the present regulatory requirements. First a manufacturing process amenable to cGMP for isolating and purifying dexosomes was established. Methods for loading the Major Histocompatibility Complex (MHC) molecules class II and I in a quantitative and reproducible way were developed. The most challenging task was the establishment of a quality control method for accessing the biological activity of individual lots. Such a method must remain relatively simple and reflect the mechanism of action of dexosomes. This was accomplished by measuring the transfer of a MHC class II superantigen complex to an antigen presenting cell that was MHC class II negative. More than 100 separate dexosome lots were prepared from blood cells of healthy volunteers to evaluate the variability of the manufacturing process. The analysis of the data showed that the main source of variability was related to the heterogeneity of the human population and not to the manufacturing process. These studies allowed to perform two phase I clinical trials. A total of 24 cancer patients received Dex therapy. Dexosome production from cells of cancer patient was found equivalent to that of normal volunteer. No adverse events related to this therapy were reported. Evidence of dexosome bioactivity was observed.

Neonatal Correlates Of Ventilatory Responses To Exercise In 8-10 Year Old Children Born With Very Low Birth Weight

PURPOSE To examine the relationships between neonatal characteristics, including birth weight (BW), days spent on mechanical ventilation (MV), and postnatal dexamethasone treatment (DEX), with ventilatory responses during exercise in children born prematurely with very low birth weight (VLBW; <1501 g), at 8–10 years of age. Treatment with DEX has documented benefits on pulmonary function in premature infants as indicated by fewer days on MV; however, long-term effects are unknown. From 2002–2003 follow-up of a randomized controlled trial of DEX therapy in VLBW children was completed. Data for 38 VLBW children who completed a maximal exercise test were analyzed for this study. Originally, 20 children (9 male) were treated postnatally with a 42-day course of DEX, and 18 children (9 male) received placebo (CON). METHODS Neonatal data were retrieved from a research database. Each child performed a graded maximal exercise test on a cycle ergometer. Ventilatory responses were measured breath-by-breath via a MedGraphics metabolic cart and included minute ventilation (VE), respiratory rate (bf), and tidal volume (VT) at peak exercise. The nadir of the ventilatory equivalent for carbon dioxide (VE/VCO2nad) was determined to reflect submaximal ventilatory efficiency. RESULTS BW was positively correlated with VE (r = .698, P = .001) and VT (r = .531, P = .023) and negatively correlated with VE/VCO2nad (r = −.509, p = .031) for the CON group only. Spearman correlations revealed a positive trend between time spent on MV and VE/VCO2nad (r = .450, P = .061) in the CON group. Among the DEX group, no significant correlations were observed between ventilatory responses to exercise and BW or MV. CONCLUSIONS For VLBW children not exposed to DEX therapy, higher BW was significantly associated with greater VT and VE at peak exercise, and more time spent on MV was associated with worse ventilatory efficiency during exercise as indicated by a higher VE/VCO2nad. In contrast, no neonatal characteristics were correlated with ventilatory responses to exercise in the DEX group. Our results found no detrimental effects of postnatal DEX exposure, and it appears that DEX disrupts the association between neonatal indices of lung function (MV) and ventilatory efficiency during exercise at school-age. Further research is warranted to determine correlates of ventilatory responses to exercise and subsequent exercise tolerance in VLBW children treated postnatally with DEX. Supported by General Clinical Research Center Grant RR M0107122, the WFU Science Research Fund, and Brenner Children's Hospital Intramural Funding.

Neonatal Correlates Of Ventilatory Responses To Exercise In 8-10 Year Old Children Born With Very Low Birth Weight

PURPOSE To examine the relationships between neonatal characteristics, including birth weight (BW), days spent on mechanical ventilation (MV), and postnatal dexamethasone treatment (DEX), with ventilatory responses during exercise in children born prematurely with very low birth weight (VLBW; <1501 g), at 8–10 years of age. Treatment with DEX has documented benefits on pulmonary function in premature infants as indicated by fewer days on MV; however, long-term effects are unknown. From 2002–2003 follow-up of a randomized controlled trial of DEX therapy in VLBW children was completed. Data for 38 VLBW children who completed a maximal exercise test were analyzed for this study. Originally, 20 children (9 male) were treated postnatally with a 42-day course of DEX, and 18 children (9 male) received placebo (CON). METHODS Neonatal data were retrieved from a research database. Each child performed a graded maximal exercise test on a cycle ergometer. Ventilatory responses were measured breath-by-breath via a MedGraphics metabolic cart and included minute ventilation (VE), respiratory rate (bf), and tidal volume (VT) at peak exercise. The nadir of the ventilatory equivalent for carbon dioxide (VE/VCO2nad) was determined to reflect submaximal ventilatory efficiency. RESULTS BW was positively correlated with VE (r = .698, P = .001) and VT (r = .531, P = .023) and negatively correlated with VE/VCO2nad (r = −.509, p = .031) for the CON group only. Spearman correlations revealed a positive trend between time spent on MV and VE/VCO2nad (r = .450, P = .061) in the CON group. Among the DEX group, no significant correlations were observed between ventilatory responses to exercise and BW or MV. CONCLUSIONS For VLBW children not exposed to DEX therapy, higher BW was significantly associated with greater VT and VE at peak exercise, and more time spent on MV was associated with worse ventilatory efficiency during exercise as indicated by a higher VE/VCO2nad. In contrast, no neonatal characteristics were correlated with ventilatory responses to exercise in the DEX group. Our results found no detrimental effects of postnatal DEX exposure, and it appears that DEX disrupts the association between neonatal indices of lung function (MV) and ventilatory efficiency during exercise at school-age. Further research is warranted to determine correlates of ventilatory responses to exercise and subsequent exercise tolerance in VLBW children treated postnatally with DEX. Supported by General Clinical Research Center Grant RR M0107122, the WFU Science Research Fund, and Brenner Children's Hospital Intramural Funding.

Short‐ and long‐term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone?

Aim: To compare short‐term effects and neurodevelopmental outcome of neonatal glucocorticoid therapy between two centres. Methods: A retrospective study was performed in two centres using a tapering course of either 5 to 1 mgkg−1 hydrocortisone (HC; 22 d) or 0.5 to 0.1 mg kg−1 dexamethasone (DEX; 21 d). In both centres glucocorticoid‐treated infants and control patients were matched for gestational age, birthweight, severity of infant respiratory distress syndrome and periventricular‐intraventricular haemorrhage. The following short‐term glucocorticoid‐induced effects were investigated in 25 HC‐treated and 25 control patients in centre A, and in 23 DEX‐treated and 23 control patients in centre B: oxygen dependency (inspiratory oxygen fraction), arterial pressure, blood glucose and urea concentrations, weight gain and head circumference before, during and after therapy (in treated infants), or at an interval comparable to treated infants (in control infants). Neurological outcome, psychomotor development and school performance at 5–7 y of age was evaluated in all groups. Results: HC and DEX were equally potent in reducing oxygen dependency. Mean arterial pressure as well as blood glucose and urea concentrations were significantly increased during DEX, but not during HC treatment. Weight gain stopped during DEX therapy, but not during HC. Head circumference in both treatment groups was decreased after therapy compared with controls. Neonatally DEX ‐treated children needed special school education significantly more often (p &lt; 0.01) than controls at 5–7 y of age. No differences between neonatally HC‐treated children and controls on neurodevelopmental outcome were found at 5–7 y of age. Conclusion: Neonatal HC therapy has fewer short‐ and long‐term adverse effects than neonatal DEX therapy.

Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone?

To compare short-term effects and neurodevelopmental outcome of neonatal glucocorticoid therapy between two centres. A retrospective study was performed in two centres using a tapering course of either 5 to 1 mg kg(-1) hydrocortisone (HC; 22 d) or 0.5 to 0.1 mg kg(-1) dexamethasone (DEX; 21 d). In both centres glucocorticoid-treated infants and control patients were matched for gestational age, birthweight, severity of infant respiratory distress syndrome and periventricular-intraventricular haemorrhage. The following short-term glucocorticoid-induced effects were investigated in 25 HC-treated and 25 control patients in centre A, and in 23 DEX-treated and 23 control patients in centre B: oxygen dependency (inspiratory oxygen fraction), arterial pressure, blood glucose and urea concentrations, weight gain and head circumference before, during and after therapy (in treated infants), or at an interval comparable to treated infants (in control infants). Neurological outcome, psychomotor development and school performance at 5-7 y of age was evaluated in all groups. HC and DEX were equally potent in reducing oxygen dependency. Mean arterial pressure as well as blood glucose and urea concentrations were significantly increased during DEX, but not during HC treatment. Weight gain stopped during DEX therapy, but not during HC. Head circumference in both treatment groups was decreased after therapy compared with controls. Neonatally DEX-treated children needed special school education significantly more often (p < 0.01) than controls at 5-7 y of age. No differences between neonatally HC-treated children and controls on neurodevelopmental outcome were found at 5-7 y of age. Neonatal HC therapy has fewer short- and long-term adverse effects than neonatal DEX therapy.

Effect of antenatal dexamethasone on the expression of endothelial nitric oxide synthase in the lungs of postnatal pups

Activities of endothelial nitric oxide synthase (eNOS) are developmentally regulated and its presence at birth may play a role in the transition of cardiopulmonary circulation. Antenatal dexamethasone (Dex) therapy accelerates fetal lung maturation. We speculate that Dex therapy may enhance pulmonary eNOS protein expression in the newborn. This article examines whether antenatal Dex therapy affected the expression of eNOS in the lungs of rat pups in the postnatal period. Time-dated pregnant Wistar rats were subjected to 2 doses of Dex (0.8 mg/kg, intramuscularly, daily) or equivalent volume of normal saline at the 18th and 19th gestational day and delivered naturally. The newborn pups were randomly assigned to 4 groups by age: days 1, 3, 5, and 7. After homogenization, abundance of eNOS protein in lungs was determined by Western blot analysis. There were 7 dams in each group. Mean body weights of the pups in the Dex group were lighter than those in the control at birth and remained stunted up to day 7 (5.68+/-0.47 g v 6.34+/-0.47 g, P <.01). However, there were no differences in wet lung weights and lung/body weight ratios between both groups in the study period. Abundance of eNOS protein expression decreased in both the control and Dex groups (P < .01). Pups that received antenatal Dex had 39% more in abundance of eNOS protein expression in lungs when compared to the control on day 1 (P < .05) but there were no differences between both groups from day 3 to 7. We conclude that antenatal Dex therapy enhances the abundance of eNOS protein expression in the lung at birth and could be a factor in improving respiratory functions in infants who received antenatal steroid therapy.

Cerebrospinal fluid cytokine levels and dexamethasone therapy in bacterial meningitis.

cerebrospinal fluid (CSF) levels of interleukin (IL)-1 beta and tumor necrosis factor (TNF) alpha were measured to assess the effect and application of dexamethasone (Dex) therapy for bacterial meningitis. associations between clinical findings and CSF parameters were first investigated, and prognosis was compared between 25 patients with Dex and 12 without Dex therapy. patients with the presence of disturbed consciousness showed higher CSF levels of TNF alpha (mean: 3015 pg/ml) or protein (mean: 215 mg/dl) than those without it (both, P < 0.O5). Simultaneous increase of TNF alpha (> 1000 pg/ml) and protein (> 100 g/dl) was observed in 80%, of patients with profoundly disturbed consciousness. Patients with Dex therapy presented higher TNF alpha/protein levels at diagnosis than those without Dex therapy (P < 0.05). Despite worse conditions at diagnosis, only one of 14 Dex-treated patients whose initial CSF TNF alpha levels exceeded 1000 pg/ml developed deafness. On the other hand, two of four patients without Dex therapy who had the same TNF alpha level suffered from psychomotor retardation. The differences in the frequency of sequelae between those with and without Dex therapy were significant in patients showing high TNF alpha level (P < O.05), but not in those showing high CSF levels of IL-1 beta or protein. The logistic regression analysis indicated that high CSF protein level (P < O.0001), or no Dex therapy (P=0.0001) was the independent risk factor for sequelae. although the study number was small, our observations suggested that CSF TNF alpha/protein levels reflected the neurologic severity, and implied that early Dex therapy might be beneficial for patients with prominently high TNF alpha levels.

Meta-Analyses of Dexamethasone (Dex) Therapy Started in the First 15 Days of Life for Prevention of Chronic Lung Disease (CLD) in Premature Infants. 951

Meta-Analyses of Dexamethasone (Dex) Therapy Started in the First 15 Days of Life for Prevention of Chronic Lung Disease (CLD) in Premature Infants. 951

Infections Among Very Low Birthweight Infants Enrolled in the NICHD Neonatal Research Network Dexamethasone (Dex) Trial • 1482

Background: A multicenter randomized trial comparing the effects of dex therapy initiated at 14 or 28 days of life in VLBW (501-1500g) infants at risk for chronic lung disease (CLD) was conducted by the NICHD Neonatal Research Network. Group 1 received dex on study days 1-14 and placebo on study days 14-28. Group 2 received placebo on study days 1-14 and steroids, if needed, on study days 14-28. Group 2 infants with minimal or no ventilator dependence on study day 14 continued to receive placebo to study day 28.Purpose: To assess the relation of dex and other factors to definite or possible/clinical infection. Methods: Data on suspicion of infection, cultures performed, and antibiotic therapy were collected daily for 42 days after randomization. Infectious complications were evaluated for study days 1-14 and 1-42. Findings: 371 patients were enrolled. Group 1 (n=182) and Group 2 (n=189) had similar baseline risk factors for infection. During the first 14 days, Group 1 infants were significantly more likely than Group 2 infants to have a positive blood culture (36% vs 24%, p=0.012) and a definite infection (22% vs 14%, p=0.038). Over the 6-week study period, 42% of all infants had at least one positive blood culture (Group 1, 46% vs. Group 2, 38%, p=0.12) and 25% of infants were judged to have one or more definite infections (Group 1, 29% vs. Group 2, 21%, p=0.08). Among patients who were cultured, infants in Group 1 were significantly more likely to have a positive blood culture than were those in Group 2 (53% vs. 41%, p=0.02). Factors present at the time of randomization (including BW, GA, race, sex, prenatal steroids, C/S, sepsis hx, severity of RDS, medications given and treatment assignment) were evaluated for their association with subsequent infection. Using logistic regression models, randomization to Group 1 and antacid/H2 blocker therapy were both associated with an increased risk of definite infection for days 1-14 and antacid/H2 blocker treatment increased risk for the entire study period. Increasing birthweight and C/S delivery were both associated with a decreased risk of definite infection.Conclusion: Contrary to the findings of smaller trials, infection was more common in patients randomized to dex than placebo during the first 2 study weeks. In addition, the risk of infection over the entire 42-day study period was higher when dex was started at 2 weeks of age than when dex was started at 4 weeks of age, if needed. The decision to treat VLBW infants with or at risk for CLD with dex must be based on a balance of potential benefits and risks.

Suppression and recovery of the neonatal hypothalamic-pituitary-adrenal axis after prolonged dexamethasone therapy

Objective: To evaluate the duration and level of hypothalamic-pituitary-adrenal (HPA) axis suppression in premature infants treated with a prolonged course of glucocorticoids for chronic lung disease.Study design: We evaluated HPA axis function in nine very low birth weight (VLBW) infants before and 48 hours after a prolonged (14 to 42 days) dexamethasone (Dex) course. Seven of these infants underwent serial testing in the Clinical Research Center to evaluate the time course of HPA axis recovery. Adrenal function was assessed directly with synthetic adrenocorticotropic hormone (ACTH) stimulation, pituitary function with ovine corticotrophin releasing hormone (oCRH) stimulation, and combined axis function with 3-hour metyrapone testing.Results: Baseline cortisol values were higher before Dex therapy (18.6 ± 3.9 μg/dl; mean ± SEM) than after (5.77 ± 1.45 μg/dl; p < 0.01), as were ACTH-stimulated cortisol levels (24.8 ± 1.7 μg/dl vs 12.0 ± 2.2 μg/dl; p < 0.001). ACTH response to oCRH decreased after Dex treatment (22.8 ± 7.6 ρg/ml vs 11.5 ± ρg/ml), but this was not statistically significant ( p = 0.18). 11-Deoxycortisol (11-DOC) response to metyrapone dropped from 11.1 ± 0.5 μg/dl to 4.7 ± 1.0 μg/dl after Dex therapy ( p < 0.0001).Longitudinal testing reveals that adrenal suppression may be short-lived, while recovery of higher centers is more delayed.Conclusions: Basal cortisol levels may be used as a screening test, but if the level is less than 15 μg/dl, more definitive testing should be performed. The sluggish recovery of higher HPA axis centers is most reliably evaluated by using 11-DOC response to a single dose of metyrapone in VLBW infants after prolonged Dex therapy. (J Pediatr 1997;131:722-26)

HORMONAL MONITORING AND SIDE EFFECTS OF PRENATAL DEXAMETHASONE (DEX) TREATMENT FOR 21-HYDROXYIASE DEFICIENCY CONGENITAL ADRENAL HYPERPIASIA (CAH)

Maternal Dex therapy for fetal CAH at 1-1.5 mg daily initiated between 5-8 weeks gestation and continued to birth, resulted in normal genital outcome, mild virilization, and significant genital virilization in the three CAH newborns treated, and significant side effects in the three mothers, including excess weight gain (9-26 Ibs greater at 35-37 weeks gestation compared to previous full-term pregnancies), glucose intolerance, facial hirsutism, and Cushingoid features including moon-face, plethora, markedly discolored striae on arms, abdomen, breast, and thighs, which resulted in permanent scarring. In addition, hypertension, epigastric pain, and emotional lability were noted, but not consistently. Amniotic fluid 17-OH Progesterone, androstenedione, and testosterone, were elevated in all three Dex treated cases. Maternal EI level was consistently suppressed in the case with the normal genital outcome, and were initially unsuppressed in the cases with mild and severe genital virilization. Conclusion: Dex therapy for prenatal treatment of CAH at a dose of 1-1.5 mg daily was associated with significant maternal side effects. Amniotic fluid steroid levels may not be useful, while maternal serum E1 level may be useful for therapeutic monitoring of fetal CAH, this however requires further investigation.

Adrenal androgen abnormalities in women with late onset and persistent acne.

Androgens are an essential prerequisite for the development of acne. The present study was undertaken to characterize the androgen status of women with late onset and persistent acne only and, using the dexamethasone (dex) suppression test, to identify the source(s) of the androgen excess. We measured serum levels of total testosterone (T), free testosterone (FT), androstenedione (delta 4A), dihydrotestosterone (DHT), dehydroepiandrosterone sulphate (DHEA-S) and sex hormone binding globulin (SHBG) in 34 healthy control subjects, in 34 women with mild acne and in 29 women with moderate or severe acne. Serum FT, DHT and DHEA-S levels in patients of both acne groups were significantly higher than those in the control subjects. The other hormone levels showed no significant differences between patients and control subjects, and there were no significant differences between the two acne groups in any of the androgen levels. In order to evaluate the ovarian and adrenal contributions to serum androgens in the acne patients, the serum levels of delta 4A, T, DHT and DHEA-S were measured prior to and following 2 weeks of dex therapy. Following the dex test, the DHT and T of adrenal origin were significantly higher in the acne patients than in the control subjects. These results suggest that, in acne patients, hyperandrogenaemia is likely to develop as a result of adrenal androgen excess. In addition, since abnormally high androgen levels are frequently seen in late onset and persist acne, it seems that this condition is likely to be a sign of hyperandrogenism.

Dexamethasone therapy for bronchopulmonary dysplasia: improved respiratory mechanics without adrenal suppression.

The purpose of the present study was to examine the pattern of changes in respiratory system mechanics induced by dexamethasone (Dex) in infants with bronchopulmonary dysplasia (BPD) and to determine whether dosages that produce these changes induce adrenal suppression. We examined mechanics in seven ventilator-dependent premature infants (age, 33 +/- 4.8 days) with BPD, before and daily during Dex therapy. Dex (0.5 mg/kg/day) was given intravenously for 7 days unless complications necessitated early termination. Respiratory system resistance (Rrs) and compliance (Crs) were measured by the passive expiratory flow-volume technique during the course of dexamethasone therapy or until extubation. Adrenocorticotrophic hormone (ACTH) stimulation tests were done at baseline and following Dex therapy to evaluate adrenal function. Dex therapy caused a 77 +/- 18% increase in Crs (from 0.97 +/- 0.09 SEM mL/cmH2O to 1.6 +/- 0.16 mL/cmH2O; P less than 0.025) and a 33 +/- 5% decrease in Rrs (from 0.20 +/- 0.02 cmH2O/mL/s to 0.14 +/- 0.01 cmH2O/mL/s; P less than 0.01). Concurrently, ventilator rate, mean airway pressure, and FIO2 all decreased significantly (P less than 0.025). Extubation occurred later in infants with the lowest Crs and highest Rrs at baseline. At extubation, all Crs values were greater than 1.33 mL/cmH2O and Rrs values were less than 0.15 cmH2O/mL/s. Systolic blood pressure increased from 61 +/- 6.3 mmHg to 84 +/- 17 mmHg, 72-96 h after the start of Dex (P less than 0.025). There were no episodes of culture-positive sepsis. Neither basal nor ACTH-stimulated levels of cortisol were suppressed as a result of Dex therapy (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

446 TREATMENT OF ANDROGEN EXCESS IN ADOLESCENT PATIENTS

Fourteen hirsute girls, ages 12-22 yrs (M±SD 17.3±2.7 yrs), in whom 21OH deficiency was excluded by 1 h° IV bolus Cortrosyn test in 1981 were evaluated by a dexamethasone (dex) suppression test (0.5 mg QID) with measurement of serum androgens on d5 and then treated with a bedtime dose of dex (0.5 mg in 10, 0.25 mg in 4) for 7-41 mos (mean 15.7 mos) with visits q3 mos. Baseline free testosterone (FT) was ↑ in 14/14 (19-57 pg/ml); DHAS > 350 ug/dl in 10/14; DHA>790 ng/dl in 8/14; Δ4 > 300 ng/dl in 5/14; urinary 17KS > 15 mg/24 h in 8/14. With the dex test DHAS↓> 50% in all (mean 70%), FT<5 pg/ml in 8/14. With dex treatment DHAS ↓21-92% (mean 51%), FT was < 15 pg/ml in only 4 patients. Hirsutism did not change in 9, ↓ in 4, and ↑ in 1 with dex therapy. Of 9 patients with irregular menses, only 3 became regular on dex. Side effects (striae, weight gain and acne) occurred in 6 on 0.5 mg dex but not on 0.25 mg. The 2 patients with the most striking clinical response to dex did not recur 14 mos and 28 mos off dex. All others off treatment showed ↑ serum androgens. 7/14 (5 with ↑ DS) not responding well to adrenal suppression responded to oral contraceptive therapy with ↓ FT 0.4-6 pg/ml and improved control of hirsutism. The data suggest that single dose dex is satisfactory in patients who maintain FT <15 pg/ml without side effects. In others with adequate suppression by dex test, other schedules or glucocorticoids may be necessary. In hirsute adolescents without adequate suppression of FT, ovarian therapy is required.

DEXAMETHASONE REDUCES VENTILATOR DEPENDENCE IN BRONCHOPULMONARY DYSPLASIA

Eight ventilator-dependent infants with clinical and radiographic BPD (birth weight 924 ± 118 grams; age 22 ± 7 days) were treated with IV dexamethasone (Dex), 0.5 mg/kg/day, for 7 days. Dex was then tapered over 2 weeks and discontinued. These infants were compared to 8 controls (birth weight 986 ± 138 grams) with improving lung disease. At study entry, treated infants had significantly increased ventilator requirements compared to controls at 14 days. Controls were extubated at age 13.3 ± 14 days. FiO2, rate, peak inspiratory pressure (PIP), and alveolar arterial oxygen differences (AaDO2) were compared before and after 7 days of Dex and to controls at age 28 days, using two-tailed Student-t test.All infants were extubated 6.1 ± 2 days after Dex treatment. Compared to 28 day controls, treated infants had higher AaDO2 (P <0.05). FiO2, ventilator requirements, and infection rates were similar in both groups. At one year of age, all Dex treated infants were alive, well, living at home, receiving neither oxygen nor diuretic therapy.Conclusion: Early Dex therapy significantly reduces ventilator dependence and may improve prognosis in developing BPD.

Effect of Dexamethasone and Clomiphene Citrate on Peripheral Steroid Levels and Ovarian Function in a Hirsute Amenorrheic Patient

A 22-year-old infertile woman with amenorrhea and mild hirsutism failed to experience uterine bleeding following withdrawal of progestin therapy and failed to ovulate or menstruate following treatment with clomiphene citrate in doses up to 200 mg/day for 5 days. Clomiphene citrate, 200 mg/day, plus 10,000 IU of human chorionic gonadotropin given on day 13 also failed to induce either ovulation or menses. Serum androgen levels were: cortisol, 186 ng/ml; dehydroepiandrosterone sulfate, 6400 ng/ml; dehydroepiandrosterone, 17.92 ng/ml; androstenedione, 4.68 ng/ml; testosterone, 1.28 ng/ml; and dihydrotestosterone, 0.75 ng/ml. Upper limits of normal values for these androgens in our laboratory are, respectively: 140, 2500, 8.0, 2.3, 0.5, and 0.35 ng/ml. The dexamethasone (Dex) suppression test indicated predominantly an adrenal source of the hyperandrogenism. Except for androstenedione the levels of all androgens measured returned to normal following treatment with 0.5 mg of Dex/day. Four months of this treatment had a beneficial effect on the hirsutism but failed to induce ovulation or menses. Clomiphene citrate, 100 mg/day for 5 days, given concurrently with Dex therapy resulted in ovulation and conception. Adrenal androgen excess has been postulated to be a cause of ovarian dysfunction. Our data support this postulate.