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In premenstrual dysphoric disorder (PMDD), a condition that afflicts 3-8 % of women in fertile ages, the cyclic recurrence of debilitating mood symptoms is restricted to the luteal phase of the menstrual cycle. The progesterone metabolite allopregnanolone is produced by the corpus luteum, and circulating levels are reflected in the brain. Allopregnanolone is a modulator of the GABA(A) receptor, enhancing the effect of gamma-aminobutyric acid (GABA). Previous studies have demonstrated different sensitivity to other GABA(A) receptor agonists, i.e., benzodiazepines, alcohol, and pregnanolone, in PMDD patients compared to controls.

This study aimed to investigate the sensitivity to intravenous allopregnanolone over the menstrual cycle in PMDD patients.

Allopregnanolone, 0.05 mg/kg, was administered intravenously once in the mid-follicular and once in the luteal phase of the menstrual cycle to 10 PMDD patients and 10 control subjects. The saccadic eye velocity (SEV) was recorded by electrooculography as a measurement of functional GABA(A) receptor activity, at baseline and repeatedly after the injection. A mixed model was used to analyze data.

There was a highly significant group x phase interaction in the SEV response to allopregnanolone (F(1,327.489) = 12.747, p < 0.001). In the PMDD group, the SEV response was decreased in the follicular phase compared to the luteal phase (F(1,168) = 7.776, p = 0.006), whereas in the control group, the difference was opposite during the menstrual cycle (F(1,158.45) = 5.70, p = 0.018).

The effect of exogenous allopregnanolone is associated with menstrual cycle phase in PMDD patients and in controls. The results suggest an altered sensitivity to allopregnanolone in PMDD patients.

The use of benzodiazepines in treating anxiety symptoms in patients with posttraumatic stress disorder (PTSD) has been debated. Studies on other anxiety disorders have indicated changed sensitivity to GABA-A receptor active substances. In the present study, we investigated the GABA receptor sensitivity in PTSD patients. Injections of allopreganolone, diazepam, and flumazenil were carried out, each on separate occasions, in 10 drug na < ve patients with PTSD compared to 10 healthy controls. Effects were measured in saccadic eye velocity (SEV) and in subjective ratings of sedation. The PTSD patients were less sensitive to allopregnanolone compared with healthy controls. This was seen as a significant difference in SEV between the groups (p = 0.047). Further, the patients were less sensitive to diazepam, with a significant less increase in sedation compared to controls (p = 0.027). After flumazenil injection, both patients and controls had a significant agonistic effect on SEV, leading to decreased SEV after injection. The patients also responded with an increase in sedation after flumazenil injection, while this was not seen in the controls. Patients with PTSD have a changed sensitivity to GABA-A receptor active substances. As a consequence of this, benzodiazepines and other GABA-A receptor active compounds such as sleeping pills will be less useful for this group of patients.

Allopregnanolone (AP) is an endogenous neurosteroid. It modulates the effect of gamma-amino-butyric acid (GABA) on the GABA type A (GABA(A)) receptor, which leads to increased receptor activity. Since the GABA-system is mainly inhibitory, increased AP activity leads to modulation of neuronal activity. In vitro studies of GABA(A) receptor activity and in vivo animal studies of sedation have shown that AP-induced effects can be inhibited by another endogenous steroid, namely isoallopregnanolone (ISO). In this study we investigated if ISO can antagonize AP-induced effects in healthy female volunteers, via measurements of saccadic eye velocity (SEV) and self-rated sedation. With a single-blind cross-over design, 12 women were studied on three separate occasions; given AP alone or AP in combination with one of two ISO doses. Congruent with previous reports, AP administration decreased SEV and induced sedation and these effects were diminished by simultaneous ISO administration. Also, the ISO effect modulation was seemingly stronger for SEV than for sedation. These effects were observed already at an ISO dose exposure that was approximately half of that of AP. In conclusion, ISO antagonized AP-induced decrease in SEV and self-reported sedation, probably in a non-competitive manner.

ObjectiveSeveral studies have reported that -aminobutyric acid (GABA) ergic circuits are involved in the pathophysiology of polycystic ovary syndrome (PCOS). The progesterone metabolite allopregnanolone is a potent GABA(A)-receptor-modulating steroid, and patients may have increased concentrations of allopregnanolone or altered GABA(A) receptor sensitivity. We investigated both of these possibilities in this study. PatientsWe enrolled 9 women with PCOS and 24 age-matched eumenorrhoeic controls, who were divided into two groups by body mass index (BMI) (16 normal weight and 8 overweight). MeasurementsWe investigated the effects of allopregnanolone injection on GABA(A) receptor sensitivity in both groups of women. All women received a single intravenous dose of allopregnanolone (0050mg/kg). GABA(A) receptor sensitivity was assessed with the saccadic eye velocity (SEV) over 30 degrees (SEV30 degrees), the SEV30 degrees/allopregnanolone concentration ([Allo]) ratio, and sedation, which were measured together with serum allopregnanolone at intervals for 180min after injection. The controls were tested in the follicular phase of the menstrual cycle. ResultsBaseline allopregnanolone concentrations were higher in the PCOS women than in the normal-weight (P=0034) and overweight controls (P=0004). The allopregnanolone concentrations after injection were higher in the PCOS women (P=0006) and overweight controls (P=0037) than in the normal-weight controls. All groups showed a decline in the SEV30 degrees/[Allo] ratio after injection. Allopregnanolone had a smaller effect on the SEV30 degrees/[Allo] ratio in the overweight women (PCOS, P=0032; controls, P=0007) than in the normal-weight controls. The sedation score after allopregnanolone injection was lower in the PCOS patients than in the controls, but was not different between the two control groups. ConclusionsPCOS women had elevated baseline allopregnanolone concentrations compared with follicular-phase controls. All overweight women (PCOS and controls) were less sensitive to allopregnanolone than normal-weight controls.

Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. Positive modulators of the GABA-A receptor include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol. GABA-A receptor modulators are known, in low concentrations to induce adverse, anxiogenic effects whereas in higher concentrations show beneficial, calming properties. Positive GABA-A receptor modulators induce strong paradoxical effects e.g. negative mood in 3-8% of those exposed, while up to 25% have moderate symptoms thus similar as the prevalence of PMDD, 3-8% among women in fertile ages, and up to 25% have moderate symptoms of premenstrual syndrome (PMS). The mechanism behind paradoxical reaction might be similar among them who react on positive GABA-A receptor modulators and in women with PMDD. In women the severity of these mood symptoms are related to the allopregnanolone serum concentrations in an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. Low to moderate progesterone/allopregnanolone concentrations in women increases the activity in the amygdala (measured with fMRI) similar to the changes seen during anxiety reactions. Higher concentrations give decreased amygdala activity similar as seen during benzodiazepine treatment with calming anxiolytic effects. Patients with PMDD show decreased sensitivity in GABA-A receptor sensitivity to diazepam and pregnanolone while increased sensitivity to allopregnanolone. This agrees with findings in animals showing a relation between changes in alpha4 and delta subunits of the GABA-A receptor and anxiogenic effects of allopregnanolone. Conclusion: These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor.

(c) 2013 Elsevier Ltd. All rights reserved.

Work related psychosocial stress can be accompanied by so called burnout syndrome with symptoms of mental exhaustion, physical fatigue, and cognitive dysfunction. Underlying mechanisms for acquiring burnout syndrome are not clear. Animal studies show that chronic stress is associated with altered release of GABA-A receptor modulating steroids (GAMS), altered composition of the GABA-A receptor and altered sensitivity to GAMS. In the present study we investigated if such changes occur in women with burnout syndrome. We further asked whether flumazenil (a benzodiazepine antagonist, but with positive modulating effects on GABA-A receptors with altered subunit composition) can block the effect of the GAMS allopregnanolone. Ten women with occupational psychosocial stress and burnout syndrome were compared with twelve healthy controls in an experimental setting. Saccadic eye velocity (SEV) was measured after an injection of allopregnanolone, followed by an injection of flumazenil and a second injection of allopregnanolone. The sensitivity to allopregnanolone was significantly higher in the patients compared to controls after the first injection (p = 0.04) and the difference increased when the response per allopregnanolone concentration unit was compared ( p = 0.006). Following the flumazenil injection the burnout patients (p= 0.016), but not controls, showed a decrease in SEV and flumazenil acted like a positive modulator that is agonistic. There was no significant difference between the groups after second allopregnanolone injection. In conclusion, patients with work related psychosocial stress and burnout syndrome show a different response to GABA-A receptor modulators than controls suggesting a changed GABA-A receptor function in these patients. More precisely we hypothesize that the alpha 4 and delta subunits are up-regulated elevating the responsiveness to allopregnanolone and change the effect of flumazenil, which provides a potential explanation to the burnout syndrome. Flumazenil does not block the effect of allopregnanolone.

Background: The purpose of this study was to investigate how women without and with different severity of premenstrual symptoms react to treatment with a combined oral contraceptive containing 250-mcg norgestimate/35-mcg ethinyl estradiol (EE). Focus was placed on mood and physical symptoms. Study Design: This open, prospective study evaluated 24 women using norgestimate/EE for three cycles in a 21/7 regimen. Symptoms and bleeding pattern were captured by daily ratings on the Cyclicity Diagnoser scale. Results: Women with severe premenstrual mood symptoms improved in summarized negative mood (p<.001) and summarized positive mood (p<.05), as well as in swelling (p<.05) and effect on daily life (p<.05). Women with no or mild or moderate symptoms did not show any significant improvement or deterioration in any symptom after 3 months of treatment. Conclusions: Norgestimate 250 mcg/EE 35 mcg significantly improved premenstrual summarized negative mood symptoms during 3 treatment months compared to pretreatment in women with severe premenstrual symptoms, together with improvement in positive symptoms, swelling and effect on daily life. (C) 2013 Elsevier Inc. All rights reserved.

Background: Induced abortion is a common medical intervention. Whether psychological sequelae might follow induced abortion has long been a subject of concern among researchers and little is known about the relationship between posttraumatic stress disorder (PTSD) and induced abortion. Thus, the aim of the study was to assess the prevalence of PTSD and posttraumatic stress symptoms (PTSS) before and at three and six months after induced abortion, and to describe the characteristics of the women who developed PTSD or PTSS after the abortion. Methods: This multi-centre cohort study included six departments of Obstetrics and Gynaecology in Sweden. The study included 1457 women who requested an induced abortion, among whom 742 women responded at the three-month follow-up and 641 women at the six-month follow-up. The Screen Questionnaire-Posttraumatic Stress Disorder (SQ-PTSD) was used for research diagnoses of PTSD and PTSS, and anxiety and depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS). Measurements were made at the first visit and at three and six months after the abortion. The 95% confidence intervals for the prevalence of lifetime or ongoing PTSD and PTSS were calculated using the normal approximation. The chi-square test and the Student's t-test were used to compare data between groups. Results: The prevalence of ongoing PTSD and PTSS before the abortion was 4.3% and 23.5%, respectively, concomitant with high levels of anxiety and depression. At three months the corresponding rates were 2.0% and 4.6%, at six months 1.9% and 6.1%, respectively. Dropouts had higher rates of PTSD and PTSS. Fifty-one women developed PTSD or PTSS during the observation period. They were young, less well educated, needed counselling, and had high levels of anxiety and depressive symptoms. During the observation period 57 women had trauma experiences, among whom 11 developed PTSD or PTSS and reported a traumatic experience in relation to the abortion. Conclusion: Few women developed PTSD or PTSS after the abortion. The majority did so because of trauma experiences unrelated to the induced abortion. Concomitant symptoms of depression and anxiety call for clinical alertness and support.

Objectives To describe the prevalence and pattern of traumatic experiences, to assess the prevalence of posttraumatic stress disorder (PTSD) and posttraumatic stress symptoms (PTSS), to identify risk factors for PTSD and PTSS, and to analyse the association of PTSD and PTSS with concomitant anxiety and depressive symptoms in women requesting induced abortion. Methods A Swedish multi-centre study of women requesting an induced abortion. The Screen Questionnaire - Posttraumatic Stress Disorder was used for research diagnoses of PTSD and PTSS. Anxiety and depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS). Results Of the 1514 respondents, almost half reported traumatic experiences. Lifetime-and point prevalence of PTSD were 7% (95% confi dence interval [CI]: 5.8-8.5) and 4% (95% CI: 3.1-5.2), respectively. The prevalence of PTSS was 23% (95% CI: 21.1-25.4). Women who reported symptoms of anxiety or depression when requesting abortion were more likely to have ongoing PTSD or PTSS. Also single-living women and smokers displayed higher rates of ongoing PTSD. Conclusions Although PTSD is rare among women who request an induced abortion, a relatively high proportion suffers from PTSS. Abortion seeking women with trauma experiences and existing or preexisting mental disorders need more consideration and alertness when counselled for termination.