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Background: Acute intermittent porphyria (AIP), a life-threatening form of the disease, is accompanied by several pain, mental and physical symptoms.

Aims: In this study, we evaluated the cyclicity of AIP and premenstrual syndrome (PMS) symptoms in 32 women with DNA-diagnosed AIP during their menstrual cycles, in northern Sweden.

Methods: The cyclicity of AIP symptoms and differences in them between the follicularand luteal phases, and the cyclicity of each symptom in each individual woman indifferent phases of her menstrual cycle were analysed with a prospective daily ratingquestionnaire. PMS symptoms were also evaluated in the patients on a daily rating scale.

Results: Of the 32 women, 30 showed significant cyclicity in at least one AIP or PMS symptom (P < 0.05–0.001). Back pain (10/32) was the most frequent AIP pain symptomand sweet craving (10/15) was the most frequent PMS symptom. Pelvic pain (F = 4.823,P = 0.036), irritability (F = 7.399, P = 0.011), cheerfulness (F = 5.563, P = 0.025), sexualdesire (F = 8.298, P = 0.007), friendliness (F = 6.157, P = 0.019), breast tenderness (F =21.888, P = 0.000) and abdominal swelling (F = 16.982, P = 0.000) showed significantcyclicity. Pelvic pain and abdominal swelling (rs= 0.337, P < 0.001) showed the strongest correlation. The age of women with latent AIP was strongly correlated with abdominal swelling during the luteal phase (rs= 0.493, P < 0.01).

Conclusion: Our results suggest that the symptoms of AIP patients change during their menstrual cycles.

Certain women experience negative mood symptoms as a result of progesterone during the luteal phase of the menstrual cycle, progestagens in hormonal contraceptives, or the addition of progesterone or progestagens in sequential hormone therapy (HT). This phenomenon is believed to be mediated via the action of the progesterone metabolites on the GABA(A) system, which is the major inhibitory system in the mammalian CNS. The positive modulators of the GABA(A) receptor include allopregnanolone and pregnanolone, both neuroactive metabolites of progesterone, as well as benzodiazepines, barbiturates, and alcohol. Studies on the effect of GABA(A) receptor modulators have shown contradictory results; although human and animal studies have revealed beneficial properties such as anaesthesia, sedation, anticonvulsant effects, and anxiolytic effects, recent reports have also indicated adverse effects such as anxiety, irritability, and aggression. It has actually been suggested that several GABA(A) receptor modulators, including allopregnanolone, have biphasic effects, in that low concentrations increase an adverse, anxiogenic effect whereas higher concentrations decrease this effect and show beneficial, calming properties. The allopregnanolone increase during the luteal phase in fertile women, as well as during the addition of progesterone in HT, has been shown to induce adverse mood in women. The severity of these mood symptoms is related to the allopregnanolone serum concentrations in a manner similar to 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. It has also been shown that progesterone/allopregnanolone treatment in women increases the activity in the amygdala (as measured with functional magnetic resonance imaging) in a similar way to the changes seen during anxiety reactions. However, it is evident that only certain women experience adverse mood during progesterone or GABA(A) receptor modulator treatments. Women with premenstrual dysphoric disorder (PMDD) have severe luteal phase related symptoms; in this phase, they show changes in GABA(A) receptor sensitivity and GABA concentrations that are related to the severity of the condition. 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. CONCLUSION: Progesterone and progestagens induce negative mood, most probably via their GABA(A) receptor active metabolites. In postmenopausal women treated with progesterone and animals treated with allopregnanolone, there is a bimodal association between serum allopregnanolone concentration and adverse mood, resembling an inverted U-shaped curve. In humans, the maximal effective concentration of allopregnanolone for producing negative mood is within the range of physiological luteal phase serum concentrations.

To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.

Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane C1(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. (C) 2011 Published by Elsevier Ltd on behalf of IBRO.

The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.

Purpose of investigation: To compare the maternal and neonatal outcomes of preterm premature rupture of the membranes (PPROM) between two management strategies. Materials and Methods: This retrospective cohort study involved 153 pregnant women who presented with PPROM at a gestational age of 28+0 to 36+6 weeks to evaluate the effects of expectant management (EM; labor > 36 hours) and active management (AM; labor < 36 hours) on maternal and neonatal outcomes. The EM and AM groups were also compared independently of gestational age and after being divided into two subgroups: early PPROM (gestational age 28+0 to 33+6 weeks) and late PPROM (34+0 to 36+6 weeks). Results: There were no differences between the AM and EM groups in the rates of maternal infection or placental abruption, or in neonatal outcomes, including low Apgar scores, respiratory distress syndrome, or the need for continuous positive airway pressure (CPAP). In the early PPROM subgroup, arterial umbilical blood base excess levels were more negative in the AM group (p = 0.007). In the late PPROM subgroup, the change in systolic blood pressure between admission to the maternity care center and membrane rupture was greater in the AM group (p = 0.049). Conclusions: There were no clinically significant differences in the maternal and neonatal outcomes of PPROM between AM and EM.

Objective To study the relation between androgen levels and sexual interest in women with different kinds of pre-menstrual syndrome (PMS). Design Causal comparative study. Setting Swedish university hospital outpatient clinic. Population Seventy women with cyclical mood changes. Methods Pre-menstrual syndrome patients were divided into those with and those without preovulatory symptoms. In 37 women, early follicular phase blood samples were analyzed for androstenedione, testosterone, sex hormone-binding globulin (SHBG), progesterone and estradiol, using radioimmunoassay. The participants were divided into subgroups depending on whether the levels of androgens and SHBG were above or below the median. In 33 of them it was possible to compare the cyclicity in sexual parameters between these subgroups. Main outcome measures Daily ratings of sexual parameters and hormonal analyses. Results Plasma testosterone was significantly lower and SHBG significantly higher in women with luteal phase symptoms compared with those with additional follicular phase symptoms. ANOVA showed significant cyclicity for all sexual parameters consistently. For the “sexual feelings” and “pleasant sexual thoughts” parameters, cyclicity was the same whether or not the hormonal levels were “high” or “low.” Conclusions The “Pure-PMS” group and the “pre-menstrual-exacerbation” groups differed in their androgen and SHBG levels. Women suffering from PMS with higher neuroticism Eysenck Personality Inventory scores or “low” levels of androgens and SHBG would be more likely to have a decreased sexual interest pre-menstrually than would women with a high level.