Injection of rats aged 3 to 9 days with hydrocortisone causes precocious development of invertase activity in the small intestine. The enzyme becomes fully active about 72 hours after injection of hydrocortisone. Invertase activity is also detectable when hydrocortisone is added to organ culture of intestine derived from 5-to 6-day old rats. Hydrocortisone does not appear to affect the activity of lactase, suggesting that it does not act solely by hastening the normal maturation process.

Epithelial cell differentiation frequently occurs in situ in conjunction with supporting mesenchyme or connective tissue. In embryonic development the importance of the supporting mesenchyme for cytodifferentiation and morphogenesis has been demonstrated in several epithelial tissues, but the importance of epithelial-connective tissue interactions is less well studied in adult epithelial organs. We have investigated the interaction of adult mammary epithelial cells with adipocytes, which compose the normal supporting connective tissue in the mammary gland. Mammary epithelial cells from mice in various physiological states were cultured on cellular substrates of adipocytes formed from cells of the 3T3-L1 preadipocyte cell line. We found that there were two distinct phases to the interaction of epithelial cells with adipocytes. Cytodifferentiation of the epithelial cells and milk protein production were dependent on lactogenic hormones (insulin, hydrocortisone, and prolactin), whereas ductal morphogenesis was lactogenic hormone independent. When cultured on preadipocytes or adipocytes, mammary epithelial cells from never pregnant, pregnant, lactating, and involuting mice responded to lactogenic hormones rapidly by producing and secreting large amounts of alpha-, beta-, and gamma-casein and alpha-lactalbumin. This response was seen in individual as well as in clusters of epithelial cells, but was not seen if the same cells were cultured on tissue culture dishes without adipocytes, on fibroblasts (human newborn foreskin fibroblasts) or in the presence of adipocytes but in the absence of lactogenic hormones. Continued incubation of mammary epithelial cells on adipocytes in the presence or absence of lactogenic hormones resulted in the formation of a branching ductal system. Mammary epithelial cells in ducts that formed in the absence of lactogenic hormones produced no casein, but rapidly synthesized casein when subsequently exposed to these hormones. Ultrastructural studies revealed that the formation of a basement membrane occurs only in co-cultures of mammary epithelium with adipocytes or preadipocytes. Ultrastructural changes associated with secretion occurred only in the presence of lactogenic hormones. We propose that growth and formation of a ductal system in vitro can occur in the absence of lactogenic hormones, but that certain environment-associated events must occur if the epithelium is to become responsive to lactogenic hormones and undergo the cytodifferentiation associated with lactation.

The aim of the present study was to examine the association between prenatal psychosocial stress exposure and subsequent prefrontal cortex-dependent working memory performance in human adults. Working memory performance was assessed using an item-recognition task under 10 mg hydrocortisone (cortisol) and placebo conditions in a sample of 32 healthy young women (mean age = 25 +/- 4.34 years) whose mothers experienced a major negative life event during their pregnancy (Prenatal Stress, PS group), and in a comparison group of 27 healthy young women (mean age = 24 +/- 3.4 years). The two groups did not differ in the placebo condition, however, subjects in the PS group showed longer reaction times after hydrocortisone administration compared with subjects in the comparison group (p = .02). These findings provide support for an association between prenatal stress exposure and the potential modulatory effect of cortisol on working memory performance in young adults, which may reflect compromised development of the prefrontal cortex in prenatal life.

Aldosterone binding sites in human mononuclear leukocytes were characterized after separation of cells from blood by a Percoll gradient. After washing and resuspension in RPMI-1640 medium, cells were incubated at 37 degrees C for 1 h with different concentrations of [3H]aldosterone plus a 100-fold concentration of RU-26988 (11 alpha, 17 alpha-dihydroxy-17 beta-propynylandrost-1,4,6-trien-3-one), with or without an excess of unlabeled aldosterone. Aldosterone binds to a single class of receptors with an affinity of 2.7 +/- 0.5 nM (means +/- SD, n = 14) and a capacity of 290 +/- 108 sites/cell (n = 14). The specificity data show a hierarchy of affinity of desoxycorticosterone = corticosterone = aldosterone greater than hydrocortisone greater than dexamethasone. The results indicate that mononuclear leukocytes could be useful for studying the physiological significance of these mineralocorticoid receptors and their regulation in humans.

Growth and function of primary cultures of granulosa cells obtained from immature, hypophysectomized, estrogen-treated rats were compared in serum-containing and serum-free media. In serum-free medium (1:1 mixture of DMEM:F-12) supplemented with insulin, hydrocortisone, transferrin and fibronectin (4F medium), the cells remained healthy and steroidogenically responsive for at least 60 days in culture. The growth profile of the granulosa cells in 4F medium was similar to that obtained in serum-containing medium. In both media cell proliferation did not exceed more than one cell doubling. DMEM:F-12 alone did not support the cell viability. Upon FSH stimulation, the cells produced 25 fold more progestin and estrogen per cell in 4F medium than in medium supplemented with 5% serum. This effect was not directly related to serum proteins which mediate cell adhesion since cells cultured in dishes precoated with serum remained steroidogenically responsive to FSH. Cholera toxin and Bt2-cAMP readily stimulated progestin production in the presence of serum. The inhibitory effect of serum was not reversed by adding the four factors to serum-containing medium. The factors were essential for the FSH-induced steroidogenesis in serum-free medium. After four days of incubation in 4F medium, the cells showed a transient loss of their ability to produce progestin in response to FSH. In both 4F medium as well as in serum-containing medium, the cells regained their hormonal responsiveness after 35 days in culture. Since the loss of hormonal responsiveness occurred at the same time as growth was initiated in the cultures, it is suggested that the FSH-induced steroidogenesis is negatively controlled by growth-related processes.

Lymphocytes derived from the thymus (T cells) take part in the induction of humoral antibody and also effect cell-mediated graft-versus-host reactions. Preliminary treatment of mice with hydrocortisone caused an inhibition of T-cell function in humoral immunity, while enhancing the graft-versus-host reactivity of the same population of spleen cells. This suggests that different types of T cells participate in cellular and humoral immune reactions.

Over the last decade, there has been a particular interest in delivering drugs, especially peptides and proteins via the buccal route. It provides direct entry into the systemic circulation thus avoiding the hepatic first-pass effect and degradation in the gastrointestinal tract, ease of administration, and the ability to terminate delivery when required. However membrane permeation can be a limiting factor for many drugs administered via the buccal route, and the epithelium that lines the oral mucosa is a very effective barrier to the absorption of drugs. In order to deliver broader classes of drugs across the buccal mucosa, reversible methods of reducing the barrier potential of this tissue must be employed. This requisite has fostered the study of penetration enhancers that will safely alter the permeability restrictions of the buccal mucosa. It has been shown that buccal penetration can be improved by using various classes of transmucosal and transdermal penetration enhancers such as bile salts, surfactants, fatty acids and derivatives, chelators, cyclodextrins and chitosan. Among these chemicals used for the drug permeation enhancement, bile salts are most common. The first part of this paper focuses on work related to the elucidation of mechanisms of action of bile salts in buccal permeation enhancement of various drugs and mucosal irritation. In the second part, results showing the enhancing effect of chitosan on buccal permeation of hydrocortisone, a commonly used topical oral anti-inflammatory agent, and transforming growth factor beta (TGF-beta), which is a bioactive peptide to which the oral mucosa is relatively impermeable is presented.

The mammary glands of euthyroid female C3H/HeN mice undergo a series of morphological changes during development. In glands from immature animals, the epithelial component consists of a sparse ductal system with few branches which fills about one fourth of the fat pad. In the adult virgin gland, the epithelial component fills the fat pad with a highly branched ductal system and a few alveoli. In contrast, glands from adult animals maintained in a hypothyroid state by ingestion of thiouracil since weaning retain the primitive ductal appearance while filling the fat pad. The glands from animals made hyperthroid by adding 2 micrograms T4/ml drinking water have extensive lobulo-alveolar development. Glands from animals made hypothyroid during 7 weeks of involution after lactation have the same degree of deveopment as the euthyroid controls. When explants of tissue from adult hypothyroid virgin animals are cultured in serum-free medium containing insulin, hydrocortisone, and PRL, the specific milk protein, alpha-lactalbumin, is induced. The level of alpha-lactalbumin, measured as lactose synthetase activity, found per ng epithelial DNA is the same as that found in explants from glands of euthyroid virgins. These results suggest that thyroid hormones, in concert with PRL, play an important role in the regulation of development of the mouse mammary gland. Decreased levels of thyroid hormones in the serum result in retarded growth of the ductal system and little or no alveolar development. However, the resulting epithelial component of glands from hypothyroid mice is fully capable of differentiating in vitro when exposed to the proper hormonal environment.

Acute hypersensitivity reactions (HSRs) are an unpredictable and potentially catastrophic complication of treatment with chemotherapeutic agents. Reactions may affect any organ system in the body and range widely in severity from mild pruritus to systemic anaphylaxis. Certain classes of chemotherapeutic agents, such as the taxanes, platinum compounds, asparaginases, and epipodophyllotoxins are commonly associated with HSRs. The clinical characteristics of these high risk agents with respect to HSRs are discussed in this review. Protocols to prevent or reduce the severity of these reactions have been developed, but despite these attempts, HSRs will still happen. Should a reaction occur, it is imperative that it be recognised quickly in order to minimise exposure to the inciting agent and implement appropriate therapeutic and supportive measures. When a patient becomes sensitised to a chemotherapeutic agent, avoidance of re-exposure is the mainstay of future prevention. For sensitised patients who have derived clinically meaningful benefit from a particular agent, however, continuation of treatment with the agent is desirable. Options may include attempting a trial of desensitisation or treatment with a related compound. Virtually all patients demonstrating HSRs to paclitaxel and docetaxel are able to successfully tolerate re-treatment following discontinuation and administration of diphenhydramine and hydrocortisone. Re-treatment has generally been less successful with platinum compounds. with recurrent HSRs occurring in up to 50% of patients following desensitisation protocols. Patients sensitised to asparaginase are often able to tolerate the alternative preparations, Erwinia carotovora asparaginase or polyethylene glycol-modified Escherichia coli asparaginase. There is very little experience with re-treatment following sensitisation to the epipodophyllotoxins. As re-treatment may have serious consequences, careful consideration of the risks and benefits of these strategies is imperative when deciding among these options.

Lactogenic hormone regulation of beta-casein gene expression in mammary epithelial cells provides an excellent model in which to study the mechanisms by which steroid and peptide hormone signaling control gene expression. Prolactin- and glucocorticoid-mediated induction of beta-casein gene expression involves two principal regulatory regions, a proximal promoter and a distal enhancer located in the mouse approximately -6 kb upstream of the transcription start site. Using a chromosome conformation capture assay and quantitative real time PCR, we demonstrate that a chromatin loop is created in conjunction with the recruitment of specific transcription factors and p300 in HC11 mammary epithelial cells. Stimulation with both prolactin and hydrocortisone is required for the induction of these long range interactions between the promoter and enhancer, and no DNA looping was observed in nontreated cells or cells treated with each of the hormones separately. The lactogenic hormone-induced interaction between the proximal promoter and distal enhancer was confirmed in hormone-treated primary three-dimensional mammary acini cultures. In addition, the developmental regulation of DNA looping between the beta-casein regulatory regions was observed in lactating but not in virgin mouse mammary glands. Furthermore, beta-casein mRNA induction and long range interactions between these regulatory regions were inhibited in a progestin-dependent manner following stimulation with prolactin and hydrocortisone in HC11 cells expressing human PR-B. Collectively, these data suggest that the communication between these regulatory regions with intervening DNA looping is a crucial step required to both create and maintain active chromatin domains and regulate transcription.

The peptide hormone, prolactin, when added to organ explants of rat mammary gland, rapidly (within 1 h) induced the accumulation of casein mRNA. Casein mRNA sequences, as determined by hybridization with a specific cDNA probe, were shown to increase for up to 48 h after prolactin addition. The magnitude of this response was dependent upon the day of pregnancy at which the tissue was placed in culture. Maximal levels of induction (as great as 45-fold) were obtained using tissue from 15-day pregnant rats. Further data indicate that two steroid hormones, hydrocortisone and progesterone, were able to modulate the prolactin-induced accumulation of casein mRNA. The continuous presence of hydrocortisone was not necessary for prolactin induction of casein mRNA. However, the presence of hydrocortisone was required for maximal accumulation of casein mRNA. The induction of casein mRNA by prolactin was inhibited in a dose-dependent manner by the simultaneous addition of progesterone to the organ culture. Thus, hydrocortisone appears to potentiate the prolactin induction of casein mRNA, whereas progesterone is able to prevent casein mRNA accumulation. Since mammary gland organ culture is performed in a serum-free, chemically defined medium, this system allows a detailed examination of the mechanims by which a peptide hormone regulates the rapid accumulation of a specific mRNA.

FK 506 therapy with low doses of steroids was adequate to control rejection in most liver recipients. Rejection episodes were readily reversed with single IV doses of methylprednisone or hydrocortisone. Short courses of OKT3 (3 to 5 days 5-10 mL) controlled severe rejections. The rate of retransplantation directly due to rejection was low (1.6%). There was a limited need for steroids either early or out to 6 to 12 months.

Interleukin-1 (IL-1) is a monocyte-derived polypeptide that mediates many host defense adaptations to environmental and infectious stresses. This investigation was intended to characterize further IL-1 activity found in human plasma following exercise (3) and to identify physiological initiators of IL-1 secretion. IL-1 activity was measured by the ability of plasma fractions to stimulate lymphocyte proliferation. This activity appeared in plasma several hours after exercise on a cycle ergometer (1 h at 60% of aerobic capacity, n = 8 subjects) and was neutralized with a specific antiserum to human IL-1. The hypothesis that IL-1 release from monocytes was initiated by phagocytosis of material from cells damaged by exercise was tested. The increase in IL-1 activity did not correlate significantly (r = 0.55) with creatine kinase activity, a marker for release of intracellular proteins into the circulation, and IL-1 secretion by monocytes was not stimulated by incubation with red blood cell lysates in vitro. Thus the stimulus for IL-1 secretion did not appear to be related to a scavenging function of monocytes. The possibility that IL-1 secretion may be mediated by stress hormones associated with exercise was examined. IL-1 secretion by monocytes was increased up to 48 +/- 18% (P less than 0.01) by addition of physiological concentrations of epinephrine in vitro. Low concentrations of hydrocortisone (1 ng/ml) also augmented IL-1 secretion by 58 +/- 20%. Higher concentrations in the physiological range had no effect, and combinations of epinephrine and hydrocortisone suppressed IL-1 secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Premature infants have higher cortisol precursor concentrations than term infants; however, many sick preterm infants have surprisingly low cortisol concentrations. Those who develop chronic lung disease (CLD) have lower cortisol values than those who recover. We hypothesized that some infants have a decreased ability to synthesize cortisol, leading to physiologic disruptions including amplified inflammatory responses, thereby resulting in CLD. We measured cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, 17-hydroxypregnenolone, dehydroepiandrosterone sulfate, and ACTH in 40 extremely low birth weight infants enrolled in a study of low-dose hydrocortisone therapy to prevent CLD. Thirty-four infants survived and 15 developed CLD. Hydrocortisone therapy did not suppress ACTH or any measured steroid value. Before study (<48 h of life), 17-OH progesterone was higher in CLD infants, as was the ratio of 17-OH progesterone to 11-deoxycortisol. On d 15-19 >> or =72 h after end of therapy), basal and stimulated cortisol concentrations were lower in CLD infants. In contrast, the basal ratio of 11-deoxycortisol to cortisol was higher in CLD infants, as were stimulated values of 17-OH progesterone and stimulated ratios of 17-OH progesterone to 11-deoxycortisol and 11-deoxycortisol to cortisol. Thus, infants who developed CLD had lower basal and stimulated cortisol values, but elevated cortisol precursors and precursor to product ratios, compared with infants who recovered. These data support the hypothesis that these immature infants have a decreased capacity to synthesize cortisol, which may lead to a relative adrenal insufficiency in the face of significant illness.

The alkaline phosphatase content of different tissue culture cell lines has been shown to vary from no detectable activity to high enzyme concentration. Within the epithelial lines studied alkaline phosphatase is either constitutive or inducible. Two epithelial cell strains in which alkaline phosphatase was "absent" could be induced to develop significant amounts of the enzyme when grown in the presence of Delta(1)-hydrocortisone. Phosphate did not repress enzyme induction by prednisolone. Under conditions of deadaptation the induced enzyme was diluted by cell multiplication. The mouse fibroblastic L line and several human fibroblastic lines did not contain alkaline phosphatase when grown under the conditions described nor could they be induced to produce the enzyme when cultivated in medium with prednisolone. Delta(1)-Hydrocortisone has other characteristic effects on established mammalian cell cultures which vary among cell lines. Human epithelial lines show reduction in cell multiplication with increase in mitotic index. The cytoplasm is increased and cell volume is nearly doubled. Mouse fibroblasts show a similar reduction in cell multiplication with a decrease in mitotic index. There is no increase in cell cytoplasm. Human fibroblast strains show no inhibition of multiplication or alteration in total cell protein when grown in medium containing prednisolone. Antisera prepared against "negative" prednisolone-inducible human cell lines and against a positive human line inhibited alkaline phosphatase activity to an equal degree.

Cell strains and cell lines rat mammary (Rama) 350-353 have been isolated from the slowly adherent stromal fraction of enzymatically digested rat mammary glands. Primary cultures of this fraction yield fat cels on extended culture. Their proportion can be increased with horse serum or growth hormone in the medium, and this increase is associated with a 100-fold or more increase in the release of radioimmunoassayable prostaglandins of the E type (PGE). The stromal cell strains and lines that are capable of yielding fat cells also secrete elevated levels (greater than 100 ng/mg/24 hr) of PGE; the fast-sticking epithelial fraction in primary cultures and the epithelial cell lines derived from it secrete 10-100 times less. Chromatography and radioisotopic labeling of the culture media from Rama 352 cells identify the PG as PGE2. PGE2 with insulin and hydrocortisone maximally stimulates [3H]DNA synthesis of epithelial cell lines and primary cultures from normal and tumorous glands by 2-4-fold at concentrations (10-20 ng/ml) well below those released by the preadipocytic stromal cells (20-100 ng/ml). Medium exposed to most cultured cells stimulates [3H]DNA synthesis of one epithelial cell line, Rama 25, by 2-4-fold. Prevention of the synthesis of PGE2 in Rama 352 cultures with indomethacin or flurbiprofen abolishes the mitogenic activity present in the culture medium, and the PG receptor antagonist polyphloretin phosphate inhibits completely the mitogenic activity for Rama 25 cells. Myoepithelial-like cell lines normally secrete moderate levels of PGE (10-100 ng/mg/24 hr) but the mitogenic activity for Rama 25 cells released from one such line, Rama 29, is not abolished by preventing the synthesis of PG's nor by PG-receptor antagonists.

BACKGROUND

Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment.

METHODS

In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat.

RESULTS

None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25.1 points), the score fell by 7.2 points for patients on hydrocortisone and by 3.3 points for those on placebo (paired difference in mean scores 4.5 points [95% CI 1.2-7.7], p=0.009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fisher's exact test p=0.05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo.

CONCLUSIONS

In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.

Four orchidectomized rhesus monkeys (3-3.5 yr of age) were treated for 62 days with daily i.m. injections of hydrocortisone acetate (HCA) at a dose of 10-20 mg/(kg BW X day), and blood samples were obtained daily or every other day before, during, and after treatment. Hydrocortisone acetate injections resulted in a progressive rise in mean plasma cortisol from basal concentrations of 17-35 micrograms/100 ml prior to initiation of steroid treatment to approximately 150 micrograms/100 ml 5 wk later. When serum cortisol concentrations reached 100 micrograms/100 ml, 3-4 wk after the initiation of HCA treatment, circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH) began to decline, reaching nondetectable concentrations 35 days later. Withdrawal of HCA resulted in a return in plasma cortisol concentrations to pretreatment control levels, which was associated with a complete restoration of gonadotropin secretion. In 2 animals, administration of an intermittent i.v. infusion of gonadotropin-releasing hormone (GnRH) (0.1 micrograms/min for 3 min once every hour), which appears to stimulate the gonadotropes in a physiologic manner, reversed the cortisol-induced inhibition of gonadotropin secretion, restoring circulating LH and FSH concentrations to within 80-100% of control. These results suggest that, in the rhesus monkey, the major site of the inhibitory action of cortisol on gonadotropin release resides at a suprapituitary level and is mediated by interruption of hypothalamic GnRH release.

OBJECTIVE

For the study of transcorneal in vitro permeation of ophthalmic drugs, excised animal cornea or corneal epithelial cell culture are frequently used as a replacement for the human cornea. The main purposes of this study were to reconstruct a complete human organotypic cornea equivalent, consisting of all three different cell types (epithelial, stromal, and endothelial); to test the barrier function of this bio-engineered human cornea using three different model drugs (pilocarpine hydrochloride (PHCl), befunolol hydrochloride (BHCl), and hydrocortisone (HC)); and to determine its usefulness as an in vitro model for prediction of ocular drug absorption into the human eye.

METHODS

A multilayer tissue construct was created step by step in Transwell cell culture insert using SV-40 immortalised human endothelial and epithelial cells and native stromal cells (fibroblasts). Morphology was characterised by light microscopy using routine H&E staining. Scanning electron microscopy was used to evaluate ultrastructural features. Ocular permeation of drugs across the human cornea construct was tested using modified Franz cells and compared with data obtained from excised porcine cornea and previously described porcine cornea constructs.

RESULTS

and conclusion: The cornea construct exhibited typical corneal structures such as a monolayer of hexagonally shaped endothelial cells and a multilayered epithelium consisting of seven to nine cell layers with flat superficial cells. The formation of microplicae and microvilli was also confirmed. The human cornea construct showed similar permeation behaviour for all substances compared with excised porcine cornea. However, permeability (permeation coefficients K(p)) of the human cornea equivalent (PHCl 13.4*10(-6) (SD 3.01*10(-6)); BHCl 9.88*10(-6) (SD 1.79*10(-6)); HC 5.41*10(-6) (SD 0.40*10(-6)) cm/s) was about 1.6-1.8 fold higher than excised porcine cornea. Compared with data from the porcine cornea construct the cultivated human equivalent showed a decreased permeability. The reconstructed human cornea could be appropriate to predict drug absorption into the human eye.

A high airway concentration might be required for the antiasthmatic efficacy of inhaled glucocorticosteroids (GCS). The topical uptake and retention of GCS in airway tissue were compared for GCS of the inhaled type [budesonide (BUD), fluticasone propionate (FP), and beclomethasone dipropionate (BDP)] and of the noninhaled type (dexamethasone and hydrocortisone). 3H-labeled GCS solutions were administered into rat airways by either perfusion of trachea in vivo, intratracheal instillation, or inhalation. Radioactivity was determined in the airway tissue, lung parenchyma, and plasma 20 min to 24 hr after exposure. Ethanol extracts of exposed tracheas were analyzed by HPLC. Exposed tracheas were also incubated in vitro in buffer, and the released radioactivity was analyzed by HPLC. BUD, FP, and BDP were equally well taken up into the airway tissue; their uptake was 25-130 times greater than that of dexamethasone and hydrocortisone. BUD was shown to form very lipophilic intracellular fatty acid esters (at carbon 21) in the airway and lung tissue after topical application. In large airways 20 min after administration, approximately 70-80% of retained BUD was conjugated. BUD stored in esterified form in the tissue was retained in large airways for a prolonged time, compared with FP and BDP, which do not form such conjugates. The fatty acid conjugation of BUD is reversible in vivo; BUD conjugates are gradually hydrolyzed and free BUD is regenerated. This reversible conjugation may improve airway selectivity, as well as prolong the local anti-inflammatory action of BUD in the airways and might be one explanation for why BUD is efficacious in the treatment of mild asthma when inhaled once daily.

OBJECTIVE

The aim of this study was to investigate the effect of low-dose hydrocortisone on glomerular permeability measured by the microalbuminuria to creatinine ratio (MACR) and on other markers of sepsis in severe septic patients.

METHODS

Randomized prospective study.

METHODS

University intensive care unit.

METHODS

The study involved 40 patients with severe sepsis randomized into the hydrocortisone group (n = 20) and the standard therapy group (n = 20).

METHODS

The hydrocortisone group received standard therapy plus a continuous infusion of hydrocortisone for 6 days, whereas the standard therapy group received only standard therapy.

RESULTS

MACR, serum C-reactive protein, and procalcitonin concentrations were recorded every day from the day before the steroid therapy (T(0)) until the 6 days after (T(1), T(2), T(3), T(4), T(5), and T(6)). Concentrations in the hydrocortisone group and the standard therapy group were compared using Mann-Whitney test at each time. We also compared with Wilcoxon signed rank test the values determined in each group at T(0) with those at each subsequent time. Median MACR decreased from T(0) to T(6) in both patient groups; however, values were significantly lower in the hydrocortisone group from T(3) through to T(6). Median serum C-reactive protein also decreased from T(0) in both patient groups, with significantly lower values in the hydrocortisone group from T(3) through to T(6). There were no significant differences in procalcitonin between groups compared with baseline values or at any individual time point.

CONCLUSIONS

Low-dose hydrocortisone seems to reduce MACR and serum C-reactive protein but not procalcitonin in patients with severe sepsis. Further studies are needed to confirm these results and to understand the underlying molecular mechanisms.

OBJECTIVE

To report repeated successful induction of fertility in an adult male patient with congenital adrenal hyperplasia (CAH) and testicular adrenal rest tumors (TART).

METHODS

Case report.

METHODS

Radboud University Nijmegen Medical Centre.

METHODS

A 23-year-old male CAH patient with bilateral TART and azoospermia.

METHODS

Changing glucocorticoid medication from 30 mg of hydrocortisone to 0.75 mg of dexamethasone (DXM) daily.

METHODS

Improved semen analysis.

RESULTS

With the use of ultrasound screening, TART were detected in the 23-year-old patient. The semen analysis showed azoospermia. In an attempt to decrease tumor size and improve testicular function, his glucocorticoid medication was changed from hydrocortisone to an equivalent dosage of DXM. The azoospermia was quickly reversed, and his partner conceived within 7 months of stopping oral contraceptives. Due to his progressive weight gain and striae, his medication was changed back to hydrocortisone, and he again developed again azoospermia. Two years later, the patient started again with DXM at the same dosage. His sperm concentration increased with progressive weight gain. Seven months later his partner became pregnant for the second time; afterward, the DXM treatment was changed back to hydrocortisone.

CONCLUSIONS

In male CAH patients with testicular adrenal rest tumors, infertility may be reversible by replacing hydrocortisone with short courses of an equivalent dosage of DXM.

Critical illness is characterized by striking alterations in the hypothalamic-anterior-pituitary-peripheral-hormone axes, the severity of which is associated with a high risk of morbidity and mortality. Most attempts to correct hormone balance have been shown ineffective or even harmful because of a lack of pathophysiologic insight. There is a biphasic (neuro)endocrine response to critical illness. The acute phase is characterized by an actively secreting pituitary, but the concentrations of most peripheral effector hormones are low, partly due to the development of target-organ resistance. In contrast, in prolonged critical illness, uniform (predominantly hypothalamic) suppression of the (neuro)endocrine axes contributes to the low serum levels of the respective target-organ hormones. The adaptations in the acute phase are considered to be beneficial for short-term survival. In the chronic phase, however, the observed (neuro)endocrine alterations appear to contribute to the general wasting syndrome. With the exception of intensive insulin therapy, and perhaps hydrocortisone administration for a subgroup of patients, no hormonal intervention has proven to beneficially affect outcome. The combined administration of hypothalamic releasing factors does, however, hold promise as a safe therapy to reverse the (neuro)endocrine and metabolic abnormalities of prolonged critical illness by concomitant reactivation of the different anterior-pituitary axes.

Pharmacologic doses of glucocorticoids are administered to patients with adrenal insufficiency during operative procedures to prevent hemodynamic instability, cardiovascular collapse, and death. Since these supraphysiologic doses might not be necessary and might have adverse effects, we examined the effects of different doses of glucocorticoids on hemodynamic adaptation during surgical stress in adrenalectomized primates. Sham-adrenalectomized placebo-treated animals served as controls. Adrenalectomized monkeys were maintained for 4 mo on physiologic glucocorticoid and mineralocorticoid replacement. The adrenalectomized monkeys were then stratified into three groups receiving, respectively, subphysiological (one-tenth the normal cortisol production rate), physiological, or supraphysiological (10 times the normal cortisol production rate) cortisol (hydrocortisone) treatment. 4 d later a cholecystectomy was performed. The intraoperative hemodynamic and metabolic parameters, perioperative survival rates, and postoperative wound healing were compared. The subphysiologically treated group was hemodynamically unstable before, during, and after surgery and had a significantly higher mortality rate than control. In this group, arterial blood pressure was low, and the cardiac index, systemic vascular resistance index, and left ventricular stroke work index were all reduced, suggesting decreased cardiac contractility and blood vessel tone. In contrast, the physiologically replaced group was indistinguishable from either supraphysiologically treated animals or sham-operated controls. All groups had similar metabolic profiles and normal wound healing. These findings suggest that the permissive actions of physiologic glucocorticoid replacement are both necessary and sufficient for primates to tolerate surgical stress. Supraphysiological glucocorticoid treatment has no apparent advantage during this form of stress in the primate.