Allopregnanolone assays.
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Chromatography, High Pressure Liquid↗
Biomedical subjects
B E Murphy
Publications and source records attributed to B E Murphy.
How much "UFC" is really cortisol?
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False Positive Reactions↗
Efficacy of light versus tryptophan therapy in seasonal affective disorder.
BACKGROUND: Although light therapy has become the accepted treatment for patients suffering from seasonal affective disorder (SAD, winter depression), almost 40% of these patients do not respond, and require an alternative treatment. METHODS: The therapeutic effects of light versus tryptophan on SAD were studied in a repeated measures design in 13 SAD patients (11 women, 2 men). Light therapy for 2 weeks or tryptophan for 4 weeks was given, separated by a one week washout period. All were assessed with the modified Hamilton Depression Rating scale (SIGH-SAD) at the beginning and end of each treatment. RESULTS: Four (31%) of the patients did not respond to either therapy. Four tryptophan-resistant patients responded to light therapy, while one light therapy-resistant patient responded to tryptophan. Relapse occurred rapidly after stopping light therapy but not after stopping tryptophan therapy. CONCLUSIONS: There were significant therapeutic effects of both light (p = 0.012) and tryptophan (p = 0.014) on SAD, which were not significantly different from each other. There may be a time difference between the residual pharmacokinetic effects after stopping therapy. LIMITATIONS: The groups studied were small. This was an open study. CLINICAL RELEVANCE: Tryptophan was equally effective to light therapy in treating SAD, but relapse after withdrawal of tryptophan probably occurs more slowly.
Adult↗
Neuroendocrine responses to inhibitors of steroid biosynthesis in patients with major depression resistant to antidepressant therapy.
OBJECTIVE: Patients with major depression frequently have high cortisol levels and resistance to dexamethasone. We sought to determine to what extent major depression might be influenced by inhibitors of steroid biosynthesis and to study the endocrine changes produced. METHOD: After drug washout, 20 treatment-resistant patients with major depression were given aminoglutethimide, metyrapone, and/or ketoconazole, along with a small dose of cortisol for 8 weeks. Hamilton Depression Rating Scale (HDRS) ratings, 8:00 AM cortisol dehydroepiandrosterone sulfate (DHAS), adrenocorticotropin (ACTH), and testosterone levels were followed weekly or oftener. A dexamethasone suppression test (DST) was conducted before and after treatment. RESULTS: Seventeen patients (85%) completed the course of treatment, and a significant mean drop (P < or = 0.0001) of 50% in the HDRS score occurred by 7 weeks of treatment. Cortisol levels fluctuated widely and were often still high after the patient had improved clinically. Dehydroepiandrosterone sulfate levels fell more uniformly and were found to be a useful indicator of compliance and, to some extent, efficacy with aminoglutethimide and ketoconazole therapy. The correlation between DHAS and HDRS (r = 0.94) was significant (P = 0.02). Testosterone levels in men fell with ketoconazole but returned promptly to normal at the end of treatment. Adrenocorticotropin levels were normal or elevated, depending on the assay used, and rose (P = 0.07; n = 13) in most subject during therapy. Of the 6 responders who had nonsuppressor DSTs before starting therapy, 5 had reverted to normal 1 to 2 weeks following cessation of therapy (P = 0.0006). CONCLUSIONS: Abnormal metabolism of adrenocortical steroids may perpetuate depression, and alterations of synthesis or metabolism of these steroids may lead to a remission.
Adult↗
Metabolism of progesterone by human lymphocytes: production of neuroactive steroids.
Although it has long been recognized that lymphocytes have the capacity to reduce cortisol at the C3, C5, and C20 positions, the specificity and the physiological variation of these reactions have received little attention. We have shown that such reactions also occur with progesterone. Lymphocytes were isolated from whole blood using Percoll density gradient centrifugation. The cells were incubated for 20 h with tritiated progesterone as radioactive tracer. After extractions into ethyl acetate, the residue was subjected to high performance liquid chromatography, and the radioactivities of the separated compounds were determined. Without cells, 95-97% of the tracer added was recovered in the progesterone peak, while in the presence of 4 x 10(6) lymphocytes, this was reduced to 45-90%. The metabolites obtained included at least 10 different compounds, including those corresponding in their retention times to the neuroactive 5 alpha and 5 beta dihydroprogesterones and their 3 alpha- and 3 beta- tetrahydroprogesterone derivatives. The conversion decreased with the addition of other steroids such as testosterone, cortisol, and corticosterone, suggesting that these steroids are metabolized by the same enzymes. When the cells from two pregnant patients were combined and incubated with tracer, and with and without nonradioactive progesterone, no peaks were detected by two progesterone radioimmunoassays in the absence of added nonradioactive progesterone, while in its presence three peaks corresponding to 5 alpha-dihydroprogesterone, 3 alpha-hydroxy-5 alpha-pregnane-20-dione and 3 beta-hydroxy-5 alpha-pregnane-20-dione eluted before the P peak. Their identities were confirmed using the two different progesterone radioassays that cross-reacted with these metabolites. The highest mean conversion (44.7% +/- 3.2 SE) was found with the lymphocytes of pregnant women and with that of one lactating woman (50%). Conversions by lymphocytes of women in the follicular phase (29.3% +/- 1.3 SE) were significantly lower than those in pregnancy (P = 0.014) but did not differ significantly (P > or = 0.05) from those of women in the luteal phase (22.2% +/- 3.4 SE), those of postmenopausal women (23.5% +/- 4.9 SE), or of men (22.5% +/- 2.4 SE). Lymphocytes appear to provide a hitherto unrecognized but possibly important source of neuroactive steroids.
Female↗
Antiglucocorticoid therapies in major depression: a review.
In major depression there are two well-documented biochemical abnormalities: hypercortisolism, and its resistance to dexamethasone suppression. It therefore seems reasonable to see if giving drugs which interfere with cortisol biosynthesis might bring about a remission. An open trial was begun in our institution of 20 refractory patients with major depression. Aminoglutethimide, metyrapone, ketoconazole or combinations of these drugs along with a maintenance dose of cortisol were used for eight weeks. Of the 17 completers, eleven patients were considered to have good responses and two partial responses. Four had complete remissions lasting several years. A similar study of four patients who received oral RU 486 also gave encouraging results. Two patients with obsessive compulsive disorder associated with depression showed striking improvement on aminoglutethimide combined with a serotonin re-uptake inhibitor. In addition to a case report in 1988 by Ravaris et al. of a patient hypophysectomized for previous Cushing's syndrome whose depression responded to ketoconazole, several other studies over the past five years have had similar favorable results. Wolkowitz et al. (1993) gave oral ketoconazole to 10 depressed patients for three weeks which resulted in a significant drop in their Hamilton Depression Scale ratings. O'Dwyer et al. (1995) conducted a placebo-controlled single-blind crossover study using lifetyrapone and maintenance cortisol in eight inpatients for two weeks; six responded. Thakore and Dinan (1995) studied eight inpatients using ketoconazole for four weeks; there were five responders and three partial responders. Anand et al. (1995) conducted a four-week double-blind trial of ketoconazole in a single treatment-refractory patient with good results. Arana et al. (1995) used a different approach but one which also leads to suppression of endogenous corticosteroids-i.e. short-term dexamethasone suppression (4 mg/day for four days). When tested at 14 days, 7/19 of the dexamethasone group had responded well while only 1/18 of the placebo group had responded. While these studies have shortcomings, antiglucocorticoid therapy appears to be an effective tool in the treatment of major depression. Possible mechanisms are discussed, and a unifying hypothesis is attempted.
Animals↗
Potentiation of fluoxetine by aminoglutethimide, an adrenal steroid suppressant, in obsessive-compulsive disorder resistant to SSRIs: a case report.
1. The role of serotonin in the aetiology of obsessive compulsive disorder (OCD) has been established through considerable indirect evidence (Landry and Chouinard, 1990). The strongest evidence comes from the fact that drugs known to be serotonin-selective reuptake inhibitors (SSRIs) have been found to be useful in the pharmacotherapy of OCD (Landry and Chouinard, 1990). 2. The authors investigated a new treatment approach by adding an adrenal steroid suppressant to a SSRI, fluoxetine, in the case of a severe obsessive-compulsive patient who was drug-resistant to clomipramine and SSRIs. 3. We found that the combination of aminoglutethimide 250 mg qid and fluoxetine 40 mg die significantly improved the patient's condition. Moreover, during a four and a half year period, each time we tried to decrease either fluoxetine or the steroid suppressant, the patient started to relapse, suggesting that the adrenal steroid suppressant had a potentiating effect on the SSRI.
Aminoglutethimide↗
The psychotropic effects of inhibitors of steroid biosynthesis in depressed patients refractory to treatment.
Twenty patients, diagnosed as suffering from treatment-resistant major depression, were treated with one or more drugs that decrease corticosteroid biosynthesis. Nine were psychotic, 11 nonpsychotic. Seventeen completed the treatment (8 psychotic, 9 nonpsychotic); 13 responded (5 psychotic, 8 nonpsychotic; 11 responded completely (i.e., a drop in the Hamilton Depression Scale of at least 50%, to < or = 15), and 2 responded partially. The mean age of the responders (45.2 +/- 12.6 years) did not differ significantly from that of the nonresponders (48.7 +/- 12/3). Data were analyzed in the following categories; (1) the presence or absence of psychosis, (2) response or nonresponse to treatment, and (3) the drug(s) used (aminoglutethimide, ketoconazole, or a combination of either of these with metyrapone). The patients improved over time on the Hamilton Depression Scale independent of the medication used. Responders demonstrated improvement in mood, insomnia, anxiety, diurnal variation, paranoia and obsessive compulsiveness. Nonpsychotics responded better than psychotics.
Adrenal Cortex Hormones↗
Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Results of the flosequinan-ACE inhibitor trial (FACET).
BACKGROUND: Angiotensin converting enzyme inhibitors, diuretics, and digoxin are each effective in treating congestive heart failure, but many patients remain symptom-limited on all three medications. This trial was designed to determine whether the addition of oral flosequinan, a new direct-acting arterial and venous vasodilator with possible dose-dependent positive inotropic effects, improves exercise tolerance and quality of life in such patients. METHODS AND RESULTS: In a randomized, double-blind multicenter trial, 322 patients with predominantly New York Heart Association class II or III congestive heart failure and left ventricular ejection fractions of 35% or less, who were stabilized on a diuretic, angiotensin converting enzyme inhibitor, and digoxin, were treated with 100 mg flosequinan once daily, 75 mg flosequinan twice daily, or matching placebo. Efficacy was evaluated with serial measurements of treadmill exercise time, responses to the Minnesota Living With Heart Failure Questionnaire (LWHF), and clinical assessments during a baseline phase and a 16-week treatment period. After 16 weeks, 100 mg flosequinan once daily produced a significant increment in median exercise time (64 seconds at 16 weeks) compared with placebo (5 seconds), whereas the higher-dose flosequinan group did not show a statistically significant increase. Flosequinan (100 mg once daily) also improved the overall LWHF score significantly compared with placebo; both active therapies decreased the physical component, but 75 mg flosequinan twice daily was associated with a trend toward worsening of the emotional component. Most clinical assessments tended to improve on active therapy. CONCLUSIONS: These results indicate that additional symptomatic benefit can be attained by adding flosequinan to a therapeutic regimen already including a converting enzyme inhibitor. Because in the future most patients will fall into this category, flosequinan is a potential adjunctive agent in the management of severe congestive heart failure. However, because recent evidence indicates that the flosequinan dose studied in the present trial has an adverse effect on survival, the benefit-to-risk ratio must be assessed in individual patients.
Adult↗
Possible use of glucocorticoid receptor antagonists in the treatment of major depression: preliminary results using RU 486.
The rationale for the use of anti-glucocorticoids in the treatment of major depression has been reviewed. Four patients with chronic severe depression who were resistant to conventional therapies were given RU 486 (200 mg/day) for periods up to eight weeks. Substantial levels of RU 486 were achieved within the first few days, and the levels fell gradually over the week after the treatment was discontinued. In three cases, treatment was stopped before the eight weeks were completed: in one case because of the appearance of a rash, in the others because of side-effects, which, in retrospect, were likely unrelated to the drug. The mean scores on the Hamilton Rating Scale for Depression of three patients decreased. Levels of adrenocorticotrophin, dehydroepiandrosterone and cortisol rose during treatment. These preliminary results suggest that glucocorticoid antagonists may be effective in the treatment of major depression and merit further exploration.
Adrenocorticotropic Hormone↗
Effect of maternal serum on viability and function of early human placental explants.
Fetal bovine serum (FBS) is frequently used to supplement chemically defined media such as Ham's F10 when studying placental explant cultures. However in vitro production of hormones is usually declining by the 2nd or 3rd day and is short-lived (7 to 10 days). In this study we explored the use of human maternal serum (HMS) from early gestation as the medium supplement to Ham's F10. Early placental hormone production was compared using two concentrations of FBS and HMS. On Day 3 of incubation, progesterone production in 10% HMS was 12-fold increased over that in 10% FBS, estradiol production was increased 10-fold, and beta hCG production more than 3-fold. When the serum concentrations were increased to 40%, the results in all cases were similar to those at 10%. Preliminary characterization studies revealed that the stimulatory activity of HMS is heat-labile, neither extractable into organic solvent (diethyl ether) nor dialyzable, suggesting that it is protein in nature. In a long-term incubation, compared with FBS (7 days), HMS permitted survival of culture up to 30 days, judged both histologically and biochemically. We conclude that HMS provides substance(s), probably protein in nature, not present in FBS or non-pregnant human serum, which are important for human placental viability and function in vivo.
Blood Physiological Phenomena↗
Influence of 19-nortestosterone and androgens on progesterone biosynthetic enzymes in early human placental explants.
We recently showed that the production of progesterone (P4) in human placental explant culture from early gestation is enhanced by treatment with 19-nortestosterone (19-NT) or with certain androgens, namely androstenedione (A-dione), 5 alpha-androstane-3 alpha,17 beta diol (3 alpha-diol) and 5 alpha-androstane-3 beta,17 beta diol (3 beta-diol). This stimulation of P4 was explored further in this study. There was little metabolism of radioactive P4 when incubated for 24 h in the presence or absence of these steroids. The role of different steroids in the regulation of P450 cholesterol side-chain cleavage enzyme (P450scc) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) was evaluated by measuring the conversion of P4 derived from unlabelled 25-hydroxycholesterol and from labelled pregnenolone, respectively. The results showed that 19-NT, A-dione and 3 alpha-diol stimulated P450scc activity; however, 3 beta-diol was ineffective. While 19-NT and 3 beta-diol enhanced the bioconversion of pregnenolone to P4, A-dione and 3 alpha-diol were without effect. The initial rapid stimulation of P4 by 19-NT within 2 h of incubation was not blocked by concurrent treatment with cycloheximide (CH). However, after incubation for 24 h, 70% of the 19-NT-stimulated P4 was abolished by CH. During the same incubation period, P4 stimulation by A-dione, 3 alpha- and 3 beta-diol were completely blocked by treatment with CH. Thus our observations suggest that 19-NT-stimulated P4 accumulation is due to the combined effects on P450scc and 3 beta-HSD enzyme activities. A-dione and 3 alpha-diol increase biosynthesis of P4 by acting selectively on P450scc enzyme. However, the stimulatory action of 3 beta-diol on P4 is only at the level of 3 beta-HSD. Since CH blocks the stimulatory actions, the mechanism(s) by which androgens (A-dione, 3 alpha-diol and 3 beta-diol) and norandrogen (19-NT) augment the biosynthetic enzyme activities appears to be mediated by a process inhibited by CH. Since CH interference was absent during the initial rapid P4-stimulation by 19-NT, there may be a direct action of this steroid at the cellular level which is not dependent on new protein synthesis.
3-Hydroxysteroid Dehydrogenases↗
In vitro stimulation of placental progesterone production by 19-nortestosterone and C19 steroids in early human pregnancy.
To explore the regulatory mechanism at the critical period of the luteal-placental shift, the effects of various steroids and peptides on the production of progesterone by placental explants at 7-10 weeks were studied. Androstenedione increased progesterone production 3-fold at a concentration of 1 mumol and more than 20-fold at 18 mumol. 19-Nortestosterone (1-18 mumol) stimulated progesterone production 10- to 100-fold. 5 alpha-Androstane-3 beta,17 beta diol (1-18 mumol) stimulated progesterone production about 2- to 5-fold while its 3 alpha isomer (1-6 mumol) increased it 2-fold. Estrone, estradiol, and estriol up to a concentration of 30 mumol had no effect. Dehydroepiandrosterone sulfate (to 36 mumol), androst-5-ene-3 beta,17 beta diol (1-6 mumol), 5 beta-androstane-3 alpha,17 beta diol (1-6 mumol), and dihydrotestosterone (1-12 mumol) had no effect. Cortisol and dexamethasone (up to 12 mumol), hCG (20,000 IU/L), GnRH (4 mumol), and ACTH 1-24 (20 mumol) also had no effect. Thus, of all the compounds tested, only 19-nortestosterone and, to a lesser extent, androstenedione, 5 alpha-androstane-3 beta,17 beta diol, and 5 alpha-androstane-3 alpha,17 beta diol stimulated progesterone production in early pregnancy; at term, only 5 alpha-androstane-3 beta,17 beta diol was stimulatory. 19-Nortestosterone was found to be less efficiently aromatized compared to other androgens; since it is also known to be present in blood from pregnant women and thought to be made in the placenta, the stimulation observed may be a paracrine effect. These observations suggest that C18 and C19 steroids may be important in the regulation of progesterone synthesis by the human placenta in early pregnancy.
Chromatography↗
Treatment of major depression with steroid suppressive drugs.
The hypercorticism frequently observed in major depression, unaccompanied by signs of Cushing's syndrome, is still poorly understood. One suicidal young woman, with very high cortisol levels and unusual resistance to dexamethasone suppression, is described. She was successfully treated with steroid suppressive drugs (aminoglutethimide, metyrapone), had a prompt and complete remission and has remained well for more than two years on no medication. This success prompted an on-going clinical trial of this therapy. The available drugs and a working hypothesis of their action are discussed.
Adrenocortical Hyperfunction↗
The premenstrual syndrome and its treatment.
The premenstrual syndrome has been described briefly and the literature relating to its pathophysiology and treatment have been reviewed. The great number of theories as to etiology and many different kinds of treatments attest to our ignorance of the exact nature of this problem. Although it is obvious that the hypothalamo-pituitary-ovarian axis must be involved, the exact mechanism whereby the symptoms come about remains elusive. Progestin in the presence of estrogen appears to be essential. Excess estrogen may aggravate the condition. The popular theory of progesterone deficiency has not been supported by double blind trials of progesterone in various forms versus placebo. Because of the important placebo effect in this condition, double blind trials are essential in the assessment of any form of treatment.
Female↗
Steroids and depression.
Patients with endogenous depression (major affective disorder) frequently have high cortisol levels, but the diurnal rhythm is usually maintained and they do not develop the physical signs of Cushing's syndrome. On the other hand, depression is a frequent feature of Cushing's syndrome regardless of etiology, and it is often relieved when the cortisol levels are reduced, by whatever means. The mechanisms of the hypercortisolemia and resistance to dexamethasone suppression commonly found in endogenous depression are poorly understood; contrary to expectations, ACTH levels are not clearly elevated. There is a striking difference in the psychiatric features seen in endogenous hypercorticism compared to those seen after exogenous administration of glucocorticoids or ACTH. This suggests that either there are other stimulating or modifying factors besides ACTH or that the steroids stimulated by ACTH or other peptides differ from those in control subjects, i.e. there may be an alteration in the metabolism of steroids in depression. Little is known about the metabolic changes or the many steroids besides glucocorticoids produced by the hyperactive steroid-producing tissue. Preliminary studies suggest that major depression may be improved by steroid suppression. It is hypothesized that steroids themselves may be important in causing and perpetuating depression.
Adrenal Cortex↗
Response to steroid suppression in major depression resistant to antidepressant therapy.
Because of the similarities in the psychiatric symptoms of Cushing's syndrome and those of major depression, and because the former generally remits when the hyperadrenalism is alleviated, an open clinical trial of the effect of steroid suppression in major depression was undertaken. Ten patients satisfying the DSM-III-R criteria for major depression, and classified as treatment-resistant, were included. Eight patients completed the study, which consisted of discontinuation of other psychotropic drugs and 2 months' treatment with one or more steroid suppressive agent (aminoglutethimide, ketoconazole and/or metyrapone). Six were classified as responders, and two as partial responders. In six, the improvement has been sustained for longer than 5 months after withdrawing the drugs. Side effects were mild to moderate. These results provide some evidence that steroids are involved in the maintenance of major depression, and that their suppression may lead to a readjustment of the hypothalamic-pituitary-adrenal axis with remission of the depression.
Adult↗
Double-blind randomized crossover trial of luteal phase estrogens (Premarin) in the premenstrual syndrome (PMS).
Eleven patients with moderate to severe premenstrual syndrome were given Premarin during the latter half of the menstrual cycle for at least two cycles, and a placebo for at least two cycles. Mental and physical symptoms were monitored daily with a self-rating scale. Premarin was significantly less effective than placebo in relieving the severity of both mental (p less than 0.02) and physical (p less than 0.02) symptoms of PMS (combined data p less than 0.01). It is concluded that luteal phase Premarin is ineffective as a treatment for PMS, and may actually aggravate the symptoms.
Adult↗