Biomedical subjects
U Halbreich
Publications and source records attributed to U Halbreich.
Estrogen replacement in postmenopausal disorders.
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Plasma MHPG and age in detoxified alcoholics.
Plasma levels of 3 methoxy, 4-hydroxy phenylethyl glycol (MHPG) of detoxified alcoholics were found to be positively correlated with age as previously found with normal subjects. The slope of the regression line of plasma MHPG and age of the alcoholics in remission was significantly steeper than that of normal controls, indicating a faster age-related increase of MHPG in alcoholics.
Treatment of premenstrual syndromes with progesterone antagonists (e.g., RU-486): political and methodological issues.
The effect of political and social considerations on development and availability of medication is exemplified by the debate of the progesterone antagonist RU-486 and its indications. Premenstrual syndromes (PMS) are quite prevalent. In some women they are severe enough to warrant treatment, but at present there is no single treatment modality that has been shown to be effective with most women with PMS. Increased levels of progesterone and/or its fluctuations during the luteal phase have been suggested as possible factors in the pathophysiology of PMS. Therefore, progesterone antagonists represent a very promising avenue for treatment of a subgroup of PMS, and some other hormonally-related dysphoric disorders as well. Regretfully, because of the abortant properties of these compounds, they are the subject of a fierce debate and political considerations in the United States, and their availability for treatment trials of other indications in women is limited. It is hoped that progesterone antagonists will eventually be introduced for studies of their treatment and efficacy when indicated.
Gonadal hormones and antihormones, serotonin and mood.
Gonadal hormones influence activity of several monoaminergic neurotransmitters, and this might be one of the mechanisms by which these hormones are involved in modulation of behavior. Gonadal hormones' levels and mood fluctuate along the normal menstrual cycle; therefore, this might provide a model for the study of the interaction among hormones, mood, and other biochemical variables. The administration of gonadal hormones' antagonists ("antihormones") and the study of their central nervous system (CNS) and behavioral consequences may further elucidate hormonal-neurotransmitter interaction. We have studied several aspects of the serotonergic system along the menstrual cycle. Results show that imipramine receptor-binding in platelets is decreased in women with premenstrual dysphoric changes in the early luteal phase, 5 to 7 days before development of symptoms and shortly after the substantial periovulatory changes in gonadal hormones. The cortisol and prolactin responses to tryptophan were blunted during the late luteal phase compared with the midfollicular phase, and the cortisol, but not prolactin, responses to the serotonergic agonist 1-(m-chlorophenyl) piperazine, (mCPP) was also blunted during that period. An altered postsynaptic serotonergic responsivity might be suggested in these cases. The role of ovulation and gonadal hormones is further demonstrated by the elimination of dysphoric symptoms by the ovulation suppressant danazol.
Gonadal hormones, sex and behavior.
Gender differences have been demonstrated in several regions of the central nervous system (CNS) in animals and humans. These differences change with development and aging and are probably influenced by hormones. Gender differences have been demonstrated clinically in the prevalence of some mental disorders and responses to psychotropic medications. Gonadal hormones might be involved in these differences as well as in differential cognitive functions. The two genders also differ in the aging process. While it is well known that changes in the pituitary gonadal system influence the aging process in women, preliminary data described here demonstrate the association between pituitary-gonadal hormones and the aging process of sexual desire and activity in men. The changes in levels of gonadal hormones might contribute to the pathophysiology of dysphoric cyclic disorders and increased vulnerability to affective disorders in women. This vulnerability might be related to hormonal fluctuations over time as well as to alteration in internal oscillators and time-related functions.
Plasma melatonin levels in depressed patients before and after treatment with antidepressant medication.
Daytime melatonin was measured by radioimmunoassay in 113 depressed outpatients before and after treatment with imipramine, mianserin, phenelzine, and placebo. At baseline, elevation of daytime melatonin values above expected levels suggests nonspecificity of the assay. After 6 weeks of treatment, melatonin levels were somewhat lower in patients on imipramine, mianserin, and placebo and slightly increased in patients treated with phenelzine. Changes in melatonin levels during treatment were significantly different for phenelzine compared with the other treatments. These findings are consistent with alterations in beta-adrenergic functioning or changes in serotonin levels.
Screening and selection process for studies of menstrually-related changes.
The screening process of women who volunteered to participate in "studies of the menstrual cycle" is described. It is demonstrated that in order to arrive at a desired number of subjects who meet criteria for premenstrual changes and are in a good physical and mental status, one should recruit an extremely large number of candidates to start with. The yield of each screening procedure is presented. It is clear that fulfillment of inclusion and exclusion criteria can be obtained by a phone interview while important criteria can be clarified only by prospective monitoring of symptoms and personal structured interviews. Methods and procedures that can improve yield and decrease effort in recruitment are suggested.
Liver function, plasma dexamethasone, and DST results in detoxified alcoholics.
Alcohol abuse, alcohol withdrawal, and deterioration of hepatic function have been associated with abnormal dexamethasone suppression test (DST) results. Chronic alcohol abuse may also directly alter the pharmacokinetic disposition of dexamethasone. Plasma dexamethasone concentrations following a DST were determined in 53 detoxified alcoholics. Those with abnormal liver function had higher 4 p.m. plasma dexamethasone concentrations and lower DST cortisol concentrations. Those with normal liver function had lower plasma dexamethasone and higher DST cortisol concentrations consistent with induction of hepatic metabolic enzymes from chronic use of alcohol. The data indicate that liver function is one of the variables influencing dexamethasone disposition and DST cortisol suppression.
Hypothalamo-pituitary-adrenal activity in endogenously depressed post-traumatic stress disorder patients.
We studied the hypothalamo-pituitary-adrenal (HPA) system in Vietnam veterans with post-traumatic stress disorder (PTSD) who also met Research Diagnostic Criteria for endogenous depression (MDD-ED). Over half also abused alcohol, and many complained of pain-confounding factors usually associated with increased HPA activity. Nonetheless, not even one patient had elevated basal plasma cortisol concentrations or an abnormal dexamethasone suppression test (DST); the subjects' post-dexamethasone cortisol values and plasma cortisol per ng plasma dexamethasone were in the low-normal range. These results highlight the biological heterogeneity of endogenous depression and its possible influence by past psychological trauma, and they raise questions about the use of current typological criteria for research purposes.
Low basal levels of cortisol distinguish detoxified alcoholics with major depressive disorder from non-MDDs.
Basal plasma levels of cortisol and its suppression by dexamethasone were measured in 60 inpatient alcoholics 12-13 days after detoxification. Both hypothalamic-pituitary adrenal system parameters were essentially within normal limits in most patients--those who did not meet criteria for major depressive disorder (n = 43) as well as those who met criteria for MDD per their episode (n-17). Basal levels of cortisol below 7 micrograms/dl distinguished alcoholics without MDD from those who met criteria for MDD per current episodes.
The normalcy of self-proclaimed "normal volunteers".
Volunteers who claimed they were "healthy and normal" and did not reveal any physical or mental abnormality or medication use during brief structured interviews underwent detailed structured interviews with the Schedule for Affective Disorders and Schizophrenia. Diagnoses were based on the Research Diagnostic Criteria (RDC), and family history was determined with the Family History RDC. Of the 121 volunteers, 16.5% met criteria for diagnoses of current mental disorders. Of the 104 without current DSM-III axis I diagnoses, 35.6% had past histories and 39.4% had family histories of mental illness. These results emphasize the need for thorough assessment of "normal volunteers."
Premenstrual changes, the gentle Ms. Jekyll and the hideous Ms. Hyde: the saga of catchy titles, myths and facts.
Methodological deficiencies in studies of premenstrual syndrome (PMS) are briefly pointed out in response to a recent article. The detrimental effect of the nonsubstantiated use of the description "Ms. Hyde" in titles of articles on PMS is emphasized, even if the authors attempt to provide evidence for its disqualification.
Drug studies in women of childbearing age: ethical and methodological considerations.
Despite a recognized need for the inclusion of women of childbearing age in drug studies, many such studies include only men. This practice is due mainly to the added risk of teratogenicity and to cyclic variations in the menstrual phase and hormonal state. The methodological and ethical problems associated with drug studies in women are demonstrated by a discussion of a proposed study using lithium, a widely used drug that has been shown to have a teratogenic effect in animals and in women with bipolar affective disorder when taken chronically. Practical considerations and solutions for drug studies in women in general are suggested.
The importance of past psychological trauma and pathophysiological process as determinants of current biologic abnormalities.
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Altered plasma dexamethasone and cortisol suppressibility in patients with panic disorders.
Some abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis in patients with panic disorders were recently reported. The possibility that the disposition of dexamethasone, which has been reported to influence the Dexamethasone Suppression Test (DST), might be altered in this subgroup of patients has not, as yet, been reported. We report that 4:00 PM dexamethasone plasma concentrations following a 1-mg oral DST were significantly (p less than 0.01) lower in 23 patients with panic disorders (0.49 +/- 0.44 ng/ml) compared to 52 normal control subjects (1.09 +/- 0.64 ng/ml). This is in addition to the significantly higher (p less than 0.05) 4:00 PM postdexamethasone cortisol values per nanogram per milliliter of dexamethasone in the panic disorder patients compared to normal controls (17.7 +/- 29.6 versus 5.0 +/- 11.2 micrograms/dl). The mean percent suppression of cortisol from baseline in panic disorder was normal despite one-half the dexamethasone concentrations in these subjects. The cortisol suppression versus dexamethasone concentration curve was also shifted lower (greater fraction of cortisol suppression) and to the left (toward lower dexamethasone concentrations). These results further suggest that the HPA system is indeed altered in panic disorders, but in a manner that is not readily apparent from the DST alone.
Cortisol suppression per nanogram per milliliter of plasma dexamethasone in depressive and normal subjects.
It has been suggested that dexamethasone pharmacokinetics may affect cortisol suppression during the Dexamethasone Suppression Test (DST). In depressed patients the cortisol response has been shown to negatively correlate with dexamethasone plasma concentrations, which also influence the sensitivity and specificity of the DST. These findings have been interpreted as weakening the utility of the DST. However, the analysis of pre- and post-1 mg DST cortisol concentrations corrected for plasma dexamethasone concentrations suggest that compared with normals (n = 52), patients with major depressive disorder (MDD) as a group (n = 71) had less suppressibility of cortisol to the same plasma dexamethasone concentrations. Moreover, when the MDD patients were evaluated based on DST status, the suppressors had cortisol/dexamethasone ratios (micrograms/dl of cortisol per ng/ml of plasma dexamethasone) similar to the normal controls, whereas the nonsuppressors had ratios that were significantly higher. These data suggest that DST non-suppression, as well as sensitivity and specificity of the DST in depression, is not only attributable to altered dexamethasone disposition, but indeed, there is a genuine reduced sensitivity of cortisol to dexamethasone that still points to an abnormality of the delayed feedback mechanism of the hypothalamic-pituitary-adrenal system in some depressed patients.
Prolactin responses to haloperidol in normal young women.
The prolactin (PRL) responses to intramuscular haloperidol (HPD) (0.5, 1.0, and 1.5 mg) were evaluated in six normal premenopausal women during the follicular and luteal phases of their menstrual cycles. These were compared to the PRL responses to these doses of HPD in normal young men. PRL responses to HPD did not differ between the follicular and luteal phases. The mean log-transformed PRL response to the lowest HPD dose (0.5 mg) in women was less than that in the men, but the women had greater PRL responses than the men to the higher haloperidol doses (1.0 mg and 1.5 mg).