Identification of phase I and phase II metabolites of ketobemidone in patient urine using liquid chromatography-electrospray tandem mass spectrometry.

Ketobemidone and five of its phase I metabolites were identified in the urine of four patients post intravenous administration of Ketogan Novum. Furthermore, indications of the presence of the glucuronide conjugates of ketobemidone and norketobemidone is presented. Both hydrolyzed (beta-glucuronidase) and unhydrolyzed human urine was extracted on a mixed-mode slightly polar cation-exchange SPEC cartridge prior to analysis with LC-ESI-MS-MS. The phase I metabolites were identified by comparison of their daughter spectra with those of synthesized standards. The glucuronides were identified by their molecular mass and interpretation of the daughter spectra, as no standards were available for these compounds.

Neuroactive steroids and central nervous system disorders.

Steroid hormones are vital for the cell life and affect a number of neuroendocrine and behavioral functions. In contrast to their endocrine actions, certain steroids have been shown to rapidly alter brain excitability and to produce behavioral effects within seconds to minutes. In this article we direct attention to this issue of neuroactive steroids by outlining several aspects of current interest in the field of steroid research. Recent advances in the neurobiology of neuroactive are described along with the impact of advances on drug design for central nervous system (CNS) disorders provoked by neuroactive steriods. The theme was selected in association with the clinical aspects and therapeutical potentials of the neuroactive steroids in CNS disorders. A wide range of topics relating to the neuroactive steroids are outlined, including steroid concentrations in the brain, premenstrual syndrome, estrogen and Alzheimer's disease, side effects of oral contraceptives, mental disorder in menopause, hormone replacement therapy, Catamenial epilepsy, and neuractive steroids in epilepsy treatment.

Prevalence of psychiatric disorders in gynecologic outpatients.

OBJECTIVE: This study was undertaken to determine the point prevalence of psychiatric disorders in an unselected gynecologic population. STUDY DESIGN: Participants were 1013 consecutive women attending 2 outpatient gynecology clinics in northern Sweden between November 16 and December 15, 1998. The Primary Care Evaluation of Mental Disorders (PRIME-MD) was used as a diagnostic tool for evaluating mood, anxiety, and eating disorders. RESULTS: Overall, 897 patients (88.5%) filled in the diagnostic tool's patient questionnaire. Psychiatric disorders were present in 30.5% of the patients. Mood disorders were most common; major depression was prevalent in 10.1% of patients and minor depression was seen in 12.4% of patients. Anxiety disorders were also common and were encountered in 12.1% of patients. Among patients with a diagnosis, only 21.4% had some form of treatment. CONCLUSIONS: The prevalence of mood and anxiety disorders in an outpatient gynecology clinic is high. The majority of women with a diagnosis based on the diagnostic tool did not have a previous diagnosis and were untreated.

Endocrine response to pregnanolone.

Neuroendocrine effects of the neurosteroids, pregnanolone and allopregnanolone have been demonstrated in rats. The endocrine effects of pregnanolone in humans have so far not been fully elucidated. This study has evaluated the effects of pregnanolone administration on part of the hypothalamus-pituitary-gonadal (HPG) axis throughout the menstrual cycle in control subjects and patients with premenstrual syndrome (PMS). Intravenous pregnanolone and vehicle were given to eight women with, and eight women without, PMS during the mid-follicular and late luteal phase. Following the drug administrations, progesterone, estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin plasma levels were measured. Intravenous pregnanolone induced a rise in progesterone levels in the follicular phase. In the luteal phase progesterone levels decreased in response to pregnanolone provocation. Pregnanolone did not induce any changes in estradiol, LH, FSH or prolactin plasma levels in either cycle phase. PMS patients and control subjects did not differ with respect to the endocrine effects of pregnanolone. In conclusion, our data show that pregnanolone, in moderate doses, appears not to have any adverse effects on the HPG axis, irrespective of cycle phase.

Treatment of premenstrual syndrome with gonadotropin-releasing hormone agonist in a low dose regimen.

BACKGROUND: GnRH agonists constitute a well-documented treatment for premenstrual syndrome (PMS). However, the hypo-estrogenic state induced by the treatment renders it less suitable for long-term clinical use. The aim of the current study was to investigate the efficacy of a low dose GnRH agonist with respect to its ability to relieve premenstrual symptoms and maintain regular ovulatory cycles. METHODS: The effect of a low dose GnRH agonist (buserelin) on luteal phase symptomatology was evaluated in 27 women with severe premenstrual syndrome. The design was doubleblind, placebo-controlled and cross-over. Patients were randomized to either GnRH-agonist intranasally in a dosage of 100 microg once daily for two months or placebo for two months before the cross-over was made. The primary outcome measure consisted of daily symptom ratings for mood and physical symptoms made by the patients throughout the study. Adverse events and hormone concentrations were assessed at visits every second week. RESULTS: Premenstrual irritability and depression were significantly relieved by low dose GnRH agonist. Positive symptoms such as friendliness and cheerfulness were also improved during the premenstrual week. Likewise physical symptoms of swelling and headache displayed a significant improvement during buserelin treatment, whereas breast tenderness scores were unaffected by the treatment. The low dose GnRH agonist treatment regimen induced anovulation in as much as 56% of patients, but these subjects were significantly older than those women who maintained ovulatory cycles throughout the study. CONCLUSION: GnRH treatment significantly reduced premenstrual depression and irritability. However, low dose GnRH therapy is prone to induce anovulation, particularly with increasing age.

Lack of influence of menstrual cycle and premenstrual syndrome diagnosis on pregnanolone pharmacokinetics.

OBJECTIVE: Pregnanolone is a 3alpha-hydroxylated-5beta-reduced metabolite of the female sex steroid hormone progesterone. The compound is currently being evaluated for anaesthetic purposes. Previous studies have indicated a differential physiological response across the menstrual cycle and a different response in patients with premenstrual syndrome (PMS). This study was undertaken to determine whether hormonal changes during the menstrual cycle influence pregnanolone pharmacokinetics and to compare PMS diagnosis-related differences in pregnanolone pharmacokinetics. METHODS: Seven patients with premenstrual syndrome and seven female controls were given three increasing doses of pregnanolone in the follicular and luteal phase of the menstrual cycle. RESULTS: Mean pregnanolone elimination half-life varied between 28.4 min and 31.8 min and clearance between 59.6 ml x min(-1) x kg(-1) and 64.0 ml x min(-1) x kg(-1), depending on diagnostic group and cycle phase. No significant differences in pregnanolone pharmacokinetic properties were found between PMS patients and controls in either phase of the menstrual cycle. Furthermore, no differences in pharmacokinetic variables were detected between cycle phases. CONCLUSION: Pregnanolone pharmacokinetics do not differ between follicular and luteal phase of the menstrual cycle, nor between PMS patients and control subjects.

Patients with premenstrual syndrome have decreased saccadic eye velocity compared to control subjects.

BACKGROUND: Prior neurophysiological studies on patients with premenstrual syndrome (PMS) have revealed sleep electroencephalographic alterations in both cycle phases. We report on a study evaluating saccadic eye movements in PMS patients. METHODS: Saccadic eye movements were examined in 21 women with and 21 women without PMS on two occasions in the midfollicular and late luteal phase, respectively. On each occasion, plasma levels for estradiol, progesterone, and neuroactive progesterone metabolites were determined. RESULTS: PMS patients had decreased saccadic eye velocity (SEV) compared to control subjects. This finding was most evident in the luteal phase, whereas the difference between groups approached significance in the follicular phase. Saccade accuracy and saccade latency were not different between the two groups. Control subjects increased their SEV in the luteal phase compared to the follicular phase, whereas PMS patients did not. PMS patients rated themselves more sedated than control subjects on the testing days in both phases of the menstrual cycle. Plasma levels of gonadal hormones and neuroactive steroids did not differ between the study groups. CONCLUSIONS: The findings of a decreased SEV in PMS patients could be due to poor sleep and consequently increased sedation, but might also indicate that gamma-aminobutyric acidergic inhibition is different in patients with premenstrual syndrome.

Citalopram increases pregnanolone sensitivity in patients with premenstrual syndrome: an open trial.

We have investigated the ability of citalopram, a serotonin reuptake inhibitor, to alter the functional sensitivity to a neuroactive steroid during the late luteal phase in twelve women with premenstrual syndrome. Sensitivity to pregnanolone was assessed by comparing the effect of three increasing doses of intravenous pregnanolone on saccadic eye velocity (SEV) and self-rated sedation. Testings were performed in two consecutive menstrual cycles; without treatment and during citalopram treatment. During citalopram treatment, pregnanolone injections induced a significant SEV reduction compared to vehicle, whereas during the pre-treatment cycle there was no significant change in SEV response between vehicle and pregnanolone injections. Citalopram treatment did not alter the self-rated sedation response to pregnanolone compared to vehicle in either study cycle. These findings indicate that treatment with a selective serotonin reuptake inhibitor in the luteal phase increases the pregnanolone sensitivity in patients with premenstrual syndrome.

Patients with premenstrual syndrome have a different sensitivity to a neuroactive steroid during the menstrual cycle compared to control subjects.

We have evaluated the functional sensitivity to a neuroactive steroid in 12 women with and 12 women without premenstrual syndrome (PMS) at two stages of the menstrual cycle, by comparing the effects of three increasing doses of intravenous pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) on saccadic eye velocity (SEV) and self-rated sedation. Control subjects in the follicular and luteal phase showed a significant reduction in SEV after pregnanolone injections compared to vehicle. In PMS patients, pregnanolone injections induced a significant dose-related decrease in SEV compared to vehicle only in the follicular phase, not in the luteal phase. After pregnanolone injections, sedation scores increased significantly from vehicle among control subjects in the luteal phase but not among PMS patients in either cycle phase. High-severity PMS patients responded with less decrease in SEV and less increase in sedation scores following pregnanolone injections compared to low-severity patients. Control subjects increased their SEV response to pregnanolone in the luteal phase compared to the follicular phase, whereas PMS patients did not. These findings are compatible with a decreased GABAA-receptor sensitivity in brain areas controlling saccadic eye movements among PMS patients in the late luteal phase.

Patients with premenstrual syndrome have reduced sensitivity to midazolam compared to control subjects.

Premenstrual syndrome (PMS) depends on gonadal hormones produced by the corpus luteum. Given the facilitory actions on GABAergic inhibitory neurotransmission exerted by certain progesterone metabolites, further studies on the GABAA receptor system in premenstrual syndrome are warranted. This study evaluated the benzodiazepine sensitivity in PMS patients and control subjects, using saccadic eye velocity (SEV) and visual analogue ratings of sedation as dependent measures. PMS patients displayed a significantly reduced SEV responsiveness to benzodiazepines compared to control subjects in the follicular phase, whereas there was no difference between groups in the luteal phase. In the luteal phase, the sedation response to benzodiazepines was significantly reduced in PMS patients compared to control subjects. There was also an influence of PMS symptom severity on these measures, as high-severity PMS patients displayed blunted SEV and sedation responses to benzodiazepines compared to low-severity patients. These results indicate that PMS patients have a reduced functional sensitivity at the GABAA/benzodiazepine receptor complex throughout the menstrual cycle.

Treatment-related and treatment-independent deliveries among infertile couples, a long-term follow-up.

BACKGROUND: The aim of this hospital based long-term follow-up study was to further elucidate resolved and unresolved infertility in relation to risk factors and perinatal outcome considering treatment-related and treatment independent pregnancies. METHODS: The study included all couples attending the out-patient clinic of the Department of Gynecology in Umeå due to failure to initiate a pregnancy after at least 12 months during the period 1.1.1980-31.12.1989. Data from the Swedish Medical Birth Registry consisting of all registered births during 1.1.1980-31.12.1992 was linked to establish the number of children born. RESULTS: Six hundred and ninety-one couples were analyzed, out of which 42% had a delivery outcome. Of these women, 53% conceived in relation to given treatment whereas 47% conceived treatment-independently. Women with ovulatory disorder had a cumulative delivery rate of 82%, whereas those with unexplained infertility and tubo-peritoneal pathology displayed delivery rates of 57% and 31% respectively. Duration of infertility > 3 years was the major negative prognostic factor among patients with unexplained infertility. The frequency of premature deliveries, low birth weight and perinatal mortality was increased among patients with treatment related pregnancies. CONCLUSION: For ovulatory disorders the prognosis for a resolved infertility is good. The results among patients with tubo-peritoneal pathology emphasizes the need of in vitro fertilization in modern treatment of infertility. Unexplained infertility is accompanied with a high rate of spontaneous pregnancies but prolonged duration is a negative prognostic factor for these patients. Irrespective of diagnosis, the perinatal outcome is worse in patients with treatment-related pregnancies.

Reduced benzodiazepine sensitivity in patients with premenstrual syndrome: a pilot study.

Premenstrual syndrome (PMS) is characterized by cyclical changes in psychological and physical symptoms related to the formation of the corpus luteum and the fluctuations of gonadal hormones. Ovarian steroids have direct effects on neurotransmission, exemplified by the binding of certain metabolites of progesterone to the gamma-amino-butyric acid (GABAA) receptor where they exert a facilitating effect on inhibitory neurotransmission. There is also evidence for steroids with inverse-agonist actions on the GABAA-receptor with opposite effects on the GABAergic transmission. The purpose of this pilot study was to examine a possible decrease in GABAA/benzodiazepine-receptor sensitivity in PMS patients using saccadic eye velocity and self-ratings of sedation as dependent measures. Seven patients with proven PMS and seven control subjects were recruited for the study. Saccadic eye velocity (SEV) and visual analogue ratings for sedation and mood were measured after increasing doses of placebo and diazepam. The PMS patients responded with a significantly less decrease in saccadic eye velocity after benzodiazepine injections compared with control subjects, the difference being most prominent in the luteal phase. This group difference was due to an increased SEV responsiveness to benzodiazepines among control subjects in the luteal phase compared with the follicular phase. The PMS patients in the luteal phase responded with less increase in sedation change scores following benzodiazepine injections compared with control subjects. This group difference in the luteal phase was due to a decreased sedation response to benzodiazepines across the menstrual cycle in the PMS patients. There was no correlation between sedation change scores and SEV in PMS patients. These results support evidence for a reduced or dysregulated sensitivity at the GABAA/ benzodiazepine-receptor complex in patients with PMS.

Snowmobile injuries in Kiruna, northern Sweden.

Snowmobile injury events in Kiruna, northern Sweden, have been studied over a 3-year period. The area is large and fairly isolated with centrally located health facilities which provides a study population that reflects the actual incidence of injury events in the area. It is also a region with an extremely frequent use of snowmobiles. A series of 109 persons injured in snowmobiling crashes were analysed. The number of injury events per registered vehicles was 5/1000. There were 88 males and 21 females with the peak injury frequency in the age group 20-29 years. Six persons were under the age of 16. Most of the patients were drivers and the most common accident mechanism was falling off the machine and sudden stops. The total number of injuries were 1.1/patient. The lower extremities were the most commonly injured sites (32%). In 26% of the cases there were non-minor injuries. Nineteen patients needed in-patient care with a mean duration of hospital stay of 5.7 days. We also report four fatalities that occurred during the time of the study.