Anna-Carin Wihlbäck

Pathogenesis in menstrual cycle-linked CNS disorders.

Abstract: That 3alpha‐hydroxy‐5alpha/beta‐pregnane steroids (GABA steroids) have modulatory effects on the GABA‐A receptor is well known. In behavioral studies in animals high exogenous dosages give concentrations not usually reached in the brain under physiological conditions. Animal and human studies show that GABA‐A receptor‐positive modulators like barbiturates, benzodiazepines, alcohol, and allopregnanolone have a bimodal effect. In pharmacological concentrations they are CNS depressants, anesthetic, antiepileptic, and anxiolytic. In low dosages and concentrations, reached endogenously, they can induce adverse emotional reactions in up to 20% of individuals. GABA steroids can also induce tolerance to themselves and similar substances, and rebound occurs at withdrawal. Menstrual cycle‐linked disorders can be understood by the concept that they are caused by the action of endogenously produced GABA‐steroids through three mechanisms: (a) direct action, (b) tolerance induction, and (c) withdrawal effect. Examples of symptoms and disorders caused by the direct action of GABA steroids are sedation, memory and learning disturbance, clumsiness, increased appetite, worsening of petit mal epilepsy, negative mood as tension, irritability and depression during hormone treatments, and the premenstrual dysphoric disorder (PMDD). A continuous exposure to GABA steroids causes tolerance, and women with PMDD are less sensitive to GABA‐A modulators. A malfunctioning GABA‐A receptor system is related to stress sensitivity, concentration difficulties, loss of impulse control, irritability, anxiety, and depression. An example of withdrawal effect is “catamenial epilepsy,” when seizures increase during menstruation after the withdrawal of GABA steroids. Similar phenomena occur at stress since the adrenals produce GABA steroids during stress.

Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems.

This article will review neuroactive steroid effects on serotonin and GABA systems, along with the subsequent effects on cognitive functions. Neurosteroids (such as estrogen, progesterone, and allopregnanolone) are synthesized in the central and peripheral nervous system, in addition to other tissues. They are involved in the regulation of mood and memory, in premenstrual syndrome, and mood changes related to hormone replacement therapy, as well as postnatal and major depression, anxiety disorders, and Alzheimers disease. Estrogen and progesterone have their respective hormone receptors, whereas allopregnanolone acts via the GABA(A) receptor. The action of estrogen and progesterone can be direct genomic, indirect genomic, or non-genomic, also influencing several neurotransmitter systems, such as the serotonin and GABA systems. Estrogen alone, or in combination with antidepressant drugs affecting the serotonin system, has been related to improved mood and well being. In contrast, progesterone can have negative effects on mood and memory. Estrogen alone, or in combination with progesterone, affects the brain serotonin system differently in different parts of the brain, which can at least partly explain the opposite effects on mood of those hormones. Many of the progesterone effects in the brain are mediated by its metabolite allopregnanolone. Allopregnanolone, by changing GABA(A) receptor expression or sensitivity, is involved in premenstrual mood changes; and it also induces cognitive deficits, such as spatial-learning impairment. We have shown that the 3beta-hydroxypregnane steroid UC1011 can inhibit allopregnanolone-induced learning impairment and chloride uptake potentiation in vitro and in vivo. It would be important to find a substance that antagonizes allopregnanolone-induced adverse effects.

Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding

Depression and anxiety are common health problems affecting women, particularly during the reproductive years. Major depression is two to three times as common in women than in men. Neuroendocrine factors are likely to contribute to this overall increased risk for developing mood disorders in women, and the neuroendocrine influence is most obviously seen in women with premenstrual dysphoric disorder (PMDD) as these women experience depressed mood and anxiety premenstrually only during ovulatory cycles. Moreover, dysfunction of serotonergic transmission has been regarded as an important mechanism in several psychiatric disorders and ovarian steroids have been shown to profoundly influence the activity of the serotonergic system. Given these facts, the purpose of this study was to examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide ([3H]LSD) to the platelet 5-HT2A receptor are influenced by the cyclical changes in circulating estradiol and progesterone that occur during the menstrual cycle. We examined 28 healthy women, without oral contraceptives and with regular menstrual cycles. In the late follicular phase, Bmax for [3H]paroxetine binding was significantly higher than in the ovulatory (p<0.01), early luteal phase (p<0.05) and mid-luteal phase (p<0.01). Bmax for [3H]LSD binding was significantly higher in the early follicular phase and the early luteal phase compared to the mid-luteal phase (p<0.001 and p<0.05, respectively). In the early follicular phase and the ovulatory phase, significant correlations between estradiol serum concentrations and Kd for [3H]paroxetine were obtained (p<0.001, respectively). In the luteal phase, significant inverse correlations between progesterone as well as estradiol serum concentrations and Kd for [3H]LSD binding were found (p<0.05, respectively).

Estradiol and the addition of progesterone increase the sensitivity to a neurosteroid in postmenopausal women.

The aim of this study was to compare the pharmacodynamic response to a neuroactive steroid, pregnanolone, before and during different hormonal settings of postmenopausal hormone replacement therapy (HRT), using natural progesterone. A second aim was to investigate whether the response to pregnanolone was associated with cyclicity in negative mood symptoms during treatment. Twenty six postmenopausal women with climacteric symptoms were administered HRT in a randomized, double blinded, placebo-controlled, crossover study. The women received 2 mg oral estradiol (E(2)) continuously during two 28-day cycles and 800 mg of vaginal progesterone or placebo sequentially for the last 14 days of each treatment cycle. Pharmacodynamic response to pregnanolone was assessed before treatment, and during the last week of each treatment cycle, by comparing the effects of intravenous pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) on saccadic eye velocity (SEV), saccade acceleration, saccade latency and self-rated sedation. Throughout the study daily symptom rating scales were kept. According to the daily symptom rating scales, patients were divided into two groups; one group who displayed a significant variance in negative mood symptoms during HRT (cyclicity) and one group with no cyclical changes in negative mood symptoms during treatment. During treatment with either E(2) alone or E(2)+progesterone the response in saccadic eye movement parameters and in self-rated sedation to pregnanolone was enhanced compared to pretreatment values. The SEV, saccade acceleration and sedation responses to pregnanolone was also increased in women expressing cyclicity in negative mood symptoms compared to women with no cyclical changes in negative mood during HRT. In conclusion, during treatment with either E(2) alone, or E(2)+progesterone, pregnanolone sensitivity was increased. Women expressing cyclicity in negative mood symptoms were more sensitive to pregnanolone than women without symptom cyclicity during HRT.

Sensitivity to a Neurosteroid Is Increased during Addition of Progestagen to Postmenopausal Hormone Replacement Therapy

The aim of this study was to compare the pharmacodynamic response to a neuroactive steroid, pregnanolone, before and during different hormonal settings of postmenopausal hormone replacement therapy (HRT). Twenty-seven postmenopausal women with climacteric symptoms were administered HRT in a randomized, double-blinded, placebo-controlled crossover study. The women received 2 mg estradiol (E2) continuously during four 28-day cycles and 10 mg medroxyprogesterone acetate (MPA), 1 mg norethisterone acetate (NETA) or placebo sequentially for the last 14 days in each cycle. The pharmacodynamic response to pregnanolone was assessed before treatment and during the last week of each treatment, by comparing the effects of intravenous pregnanolone (3α-hydroxy-5β-pregnan-20-one) on saccadic eye velocity (SEV), saccade deceleration, saccade latency and self-rated sedation. Throughout the study daily symptom rating scales were kept. During the progesta gen phase of the treatment cycles, negative mood symptoms and physical symptoms were increased, whereas positive mood symptoms were decreased. Compared to pretretreatment conditions, E2 alone did not change the responsiveness to pregnanolone. During progestagen addition to E2, the responsiveness to pregnanolone was increased. The sedation response increased compared to pretreatment conditions during both E2 + MPA and E2 + NETA treatment. Compared to E2 treatment alone, addition of MPA increased the postpregnanolone effect on saccade deceleration, whereas the SEV response to pregnanolone was increased during E2 + NETA treatment. It is concluded that pregnanolone sensitivity increases together with deterioration in mood symptoms during addition of progestagen to HRT.

Influence of postmenopausal hormone replacement therapy on platelet serotonin uptake site and serotonin2a receptor binding

OBJECTIVE To examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide (LSD) to the platelet 5‐HT2A receptor are influenced by postmenopausal estrogen/progestogen treatment. METHODS Twenty‐three postmenopausal women with climacteric symptoms completed this double‐blind, randomized, crossover study. The women received 2 mg of estradiol continuously during four 28‐day cycles. In the last 14 days of each cycle, 10 mg of medroxyprogesterone acetate, 1 mg of norethindrone acetate, or placebo was given. Before treatment, as well as once during the last week of each treatment, blood samples were collected for analysis of [3H]LSD and [3H]paroxetine binding. The power of the study setup was 81%. The study had an effect size of 0.36, corresponding to the ability to detect a 15% difference in [3H]paroxetine and [3H]LSD binding between treatments with α=.05 and β=.20, based on a previously reported standard deviation within cells of 20% of the mean binding values. RESULTS The number of platelet receptors (Bmax), or the affinity of the radioligand to the receptor (Kd), for [3H]paroxetine binding did not change during estrogen or estrogen‐progestogen treatment, nor did Bmax or Kd for [3H]LSD binding change during the different treatments. However, in a subgroup of depressed patients, the decrease in Bmax for [3H]LSD binding during treatment was significantly more pronounced than in the nondepressed subgroup (P < .05). CONCLUSION Estrogen treatment with or without the addition of progestogen does not affect binding to the serotonin transporter or to the serotonergic 5‐HT2A receptor in healthy postmenopausal women.

Level of lactate in amniotic fluid and its relation to the use of oxytocin and adverse neonatal outcome.

To assess whether the frequency of adverse neonatal outcome at delivery is related to the level of lactate in amniotic fluid and to the use of oxytocin.

Allopregnanolone serum concentrations and neurosteroid sensitivity during withdrawal from postmenopausal hormone therapy

Background. We have previously compared the pharmacodynamic response to a neuroactive steroid, pregnanolone, before and during sequential treatment with estradiol-only (E2-only) and estradiol together with progesterone (E2 + P) in postmenopausal women. The aim of the present study was to evaluate the pharmacodynamic response to pregnanolone during withdrawal from E2-only treatment and during withdrawal from treatment with E2 + P. Method. Twenty-six postmenopausal women were administered hormone therapy (HT) in a randomized, double blinded, placebo-controlled, crossover study. The women received 2 mg oral estradiol continuously during two 28-day cycles and 800 mg vaginal progesterone or placebo sequentially for the last 14 days of each treatment cycle. The pharmacodynamic response to pregnanolone was assessed during the last week of the last treatment cycle and 48 h after termination of the last treatment cycle (withdrawal) by comparing the effects of intravenous pregnanolone (3α-hydroxy-5β-pregnan-20-one) on saccadic eye movements. Results. During E2-only withdrawal the pregnanolone sensitivity was reduced compared with E2-only treatment. Pregnanolone sensitivity remained unaltered between the combined E2 + P treatment regimen and the withdrawal from these steroids. Conclusion. The study indicates that withdrawal from E2-only treatment might change neurosteroid sensitivity, whereas the immediate withdrawal from E2 + P results in unchanged neurosteroid sensitivity.

Lactate in Amniotic Fluid : Predictor of Labor Outcome in Oxytocin-Augmented Primiparas' Deliveries

Background One of the major complications related to delivery is labor dystocia, or an arrested labor progress. Many dystocic deliveries end vaginally after administration of oxytocin, but a large numbers of women with labor dystocia will undergo a long and unsafe parturition. As a result of the exertion required in labor, the uterus produces lactate. The uterine production of lactate is mirrored by the level of lactate in amniotic fluid (AFL). Objectives To evaluate whether the level of AFL, analysed in a sample of amniotic fluid collected vaginally at arrested labor when oxytocin was needed, could predict labor outcome in nulliparous deliveries. Methods A prospective multicentre study including 3000 healthy primiparous women all with a singleton pregnancy, gestational age 37 to 42 weeks and no maternal /fetal chronic and/or pregnancy-related conditions. A spontaneous onset of labor, regular contractions and cervical dilation ≥ 3 cm were required before the women were invited to take part in the study. Results AFL, analysed within 30 minutes before augmentation, provides information about delivery outcome. Sensitivity for an acute cesarean section according to high (≥10.1mmol/l) or low (< 10.1mmol/l) AFL values was 39.0% (95% CI; 27–50), specificity 90.3% (95% CI; 87–93) PPV 37.3% (95% CI; 27–48) and NPV was 91.0% (95% CI; 88–93). The overall percentage of correct predictions of delivery outcome when the AFL level was used was 83.7%. Deliveries with a high AFL-level correlated with delivery time >12h (p = 0.04), post-partum fever (>38°C, p = 0.01) and post-partum haemorrhage >1.5L (p = 0.04). Conclusion The AFL is a good predictor of delivery outcome in arrested nulliparous deliveries. Low levels of AFL may support the decision to continue a prolonged vaginal labor by augmentation with oxytocin. A high level of AFL correlates with operative interventions and post-partum complications.