Allopregnanolone effects in women : clinical studies in relation to the menstrual cycle, premenstrual dysphoric disorder and oral contraceptive use

Background: Premenstrual dysphoric disorder (PMDD) affects 3–8% of women in fertile ages. Combined oral contraceptives (OCs) are widely used and some users experience adverse mood effects. The cyclicity of PMDD symptoms coincides with increased endogenous levels of allopregnanolone after ovulation. Allopregnanolone enhances the effect of γ-aminobutyric acid (GABA) on the GABAA receptor, the principal inhibitory transmitter system in the brain. The sensitivity to other GABAA receptor agonists than allopregnanolone (i.e. benzodiazepines, alcohol and the 5 β epimer to allopregnanolone, pregnanolone) has been reported to depend on menstrual cycle phase and/or PMDD diagnosis. Isoallopregnanolone, the 3 β epimer to allopregnanolone, has previously been used to verify specific allopregnanolone GABAA receptor effects. Saccadic eye velocity (SEV) is a sensitive and objective measurement of GABAA receptor function. Aims: To study the pharmacological effects, and any effect on gonadotropin release, of intravenous allopregnanolone in healthy women. A second aim was to explore whether allopregnanolone sensitivity differs over the menstrual cycle or during OC use in healthy women, and thirdly in PMDD patients. Methods: Ten women were challenged with a cumulative dose of intravenous allopregnanolone in the follicular phase of the menstrual cycle. The effect on FSH and LH was compared to women exposed to isoallopregnanolone. A single dose of allopregnanolone was administered once in the follicular phase and once in the luteal phase in another ten healthy women and in ten PMDD patients, and additionally in ten women using OCs. Repeated measurements of SEV, subjectively rated sedation and serum concentrations after allopregnanolone injections were performed in all studies. Results: Allopregnanolone dose-dependently reduced SEV and increased subjectively rated sedation. Healthy women had a decreased SEV response in the luteal phase compared to the follicular phase. By contrast, PMDD patients had a decreased SEV response and subjectively rated sedation response to allopregnanolone in the follicular phase compared to the luteal phase. There was no difference in the SEV response to allopregnanolone between women using oral contraceptives and healthy naturally cycling women. Allopregnanolone decreased serum levels of FSH and LH whereas isoallopregnanolone did not affect FSH and LH levels. Conclusion: Intravenous allopregnanolone was safely given and produced a sedative response in terms of SEV and subjectively rated sedation in women. The sensitivity to allopregnanolone was associated with menstrual cycle phase, but in the opposite direction in healthy women compared to PMDD patients. The results suggest mechanisms of physiological tolerance to allopregnanolone across the menstrual cycle in healthy women and support that PMDD patients have a disturbed GABAA receptor function. In addition, one of our studies suggests that allopregnanolone might be involved in the mechanism behind hypothalamic amenorrhea

Effects of GABA active steroids in the female brain with a focus on the premenstrual dysphoric disorder

Premenstrual dysphoric disorder (PMDD) afflicts 3%-5% of women of childbearing age, and is characterised by recurrent negative mood symptoms (eg, irritability, depression, anxiety and emotional lability) during the luteal phase of the menstrual cycle. The aetiology of PMDD is unknown, although a temporal association with circulating ovarian steroids, in particular progesterone and its metabolite allopregnanolone, has been established during the luteal phase. Allopregnanolone is a positive modulator of the GABA(A) receptor: it is sedative in high concentrations but may precipitate paradoxical adverse effects on mood at levels corresponding to luteal phase concentrations in susceptible women. Saccadic eye velocity (SEV) is a measure of GABA(A) receptor sensitivity; in experimental studies of healthy women, i.v. allopregnanolone decreases SEV. Women with PMDD display an altered sensitivity to an i.v. injection of allopregnanolone compared to healthy controls in this model. In functional magnetic resonance imaging (fMRI) studies, women with PMDD react differently to emotional stimuli in contrast to controls. A consistent finding in PMDD patients is increased amygdala reactivity during the luteal phase. Post-mortem studies in humans have revealed that allopregnanolone concentrations vary across different brain regions, although mean levels in the brain also reflect variations in peripheral serum concentrations. The amygdala processes emotions such as anxiety and aggression. This is interesting because allopregnanolone is detected at high concentrations within the region into which marked increases in blood flow are measured with fMRI following progesterone/allopregnanolone administration. Allopregnanolone effects are antagonised by its isomer isoallopregnanolone (UC1010), which significantly reduces negative mood symptoms in women with PMDD when administered s.c. in the premenstrual phase. This was shown in a randomised, placebo-controlled clinical trial in which the primary outcome was change in symptom scoring on the Daily Rating of Severity of Problems (DRSP): the treatment reduced negative mood scores (P<.005), as well as total DRSP scores (P<.01), compared to placebo in women with PMDD. In conclusion, the underlying studies of this review provide evidence that allopregnanolone is the provoking factor behind the negative mood symptoms in PMDD and that isoallopregnanolone could ameliorate the symptoms as a result of its ability to antagonise the allopregnanolone effect on the GABA(A) receptor

Allopregnanolone, a GABA-A receptor agonist, decreases gonadotropin levels in women : a preliminary study

Animal studies suggest regulatory effects on the hypothalamic-pituitary-gonad axis by allopregnanolone, an endogenous gamma-aminobutyric acid A (GABAA) receptor agonist. Elevated levels of allopregnanolone in women with hypothalamic amenorrhea have been seen. Isoallopregnanolone is an isomer to allopregnanolone, but without GABAA receptor effects. The purpose of this study was to investigate effects of allopregnanolone and isoallopregnanolone on gonadotropin levels in healthy women of fertile age. Ten women were given allopregnanolone and five women isoallopregnanolone intravenously in follicular phase. Repeated blood samples were drawn during the test day. Main outcomes were changes in serum levels of follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, and progesterone. Serum-FSH decreased between 5 and 105 min after the allopregnanolone injection (F(16,144)=2.18, p=0.008). Serum-LH was reduced between 5 and 35 min following the allopregnanolone injection (F(16,144)=2.63, p=0.001). Serum-oestradiol and -progesterone were not significantly changed after allopregnanolone injections. No effect on gonadotropin levels were seen after administration of isoallopregnanolone. Allopregnanolone reduces FSH and LH levels in women and the effect might be mediated via a specific GABAA receptor activation since isoallopregnanolone lacked this effect. Although the number of women was small, the results suggest a regulatory mechanism on the hypothalamic-pituitary-gonadal axis by allopregnanolon.Fulltext publiceras 2012-12-01</p

Abnormal birth weights for gestational age in relation to maternal characteristics in Sweden : a five year cross-sectional study

Background: Abnormal birth weight - small for gestational age (SGA) and large for gestational age (LGA) - are important indicators for newborn health. Due to changes in lifestyle in recent decades, it is essential to keep up-to-date with the latest information on maternal factors linked to abnormal birth weight. The aim of this study is to investigate SGA and LGA in relation to maternal individual, lifestyle and socioeconomic characteristics. Methods: This is a register-based cross-sectional study. Self-reported data from Sweden's Salut Programme maternal questionnaires (2010-2014) were linked with records in the Swedish Medical Birth Register (MBR). The analytical sample comprised 5089 singleton live births. A Swedish standard method using ultrasound-based sex-specific reference curves defines the abnormality of birth weight in MBR. Univariable and multivariable logistic regressions were used to examine crude and adjusted associations between abnormal birth weights and maternal individual, lifestyle and socioeconomic characteristics. A sensitivity analysis, using alternative definitions of SGA and LGA under the percentile method, was undertaken. Results: In multivariable logistic regression, maternal age and parity were associated with LGA (aOR = 1.05, CI = 1.00, 1.09) and (aOR = 1.31, CI = 1.09, 1.58). Maternal overweight and obesity were strongly associated with LGA (aOR = 2.28, CI = 1.47, 3.54) and (aOR = 4.55, CI = 2.85, 7.26), respectively. As parity increased, the odds of delivering SGA babies decreased (aOR = 0.59, CI = 0.42, 0.81) and preterm deliveries were associated with SGA (aOR = 9.46, CI = 5.67, 15.79). The well-known maternal determinants of abnormal birthweight, such as unhealthy lifestyles and poor socioeconomic factors, were not statistically significant in this Swedish setting. Conclusions: The main findings suggest that multiparity, maternal pre-pregnancy overweight and obesity are strong determinants for LGA babies. Public health interventions should address modifiable risk factors, especially maternal overweight and obesity. These findings suggest that overweight and obesity is an emerging public health threat for newborn health. This might also result in the intergenerational transfer of overweight and obesity. These are important messages for public health policy and decision making

Treatment of premenstrual dysphoric disorder with the GABA(A) receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial

Context: Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAA receptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models. Objective: The objective was to test whether inhibition of allopregnanolone by treatment with the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD). The pharmacokinetic parameters of UC1010 when given as a subcutaneous injection were measured in healthy women prior to the study in women with PMDD. Design: This was an explorative randomized, double-blind, placebo-controlled study. Setting: Swedish multicentre study with 10 centers. Participants: Participants were 26 healthy women in a pharmacokinetic phase I study part, and 126 women with PMDD in a phase II study part. Diagnosis followed the criteria for PMDD in DSM-5 using Daily Record of Severity of Problems (DRSP) and Endicott’s algorithm. Intervention: Subjects were randomized to treatment with UC1010 (10 or 16 mg) subcutaneously every second day during the luteal phase or placebo during one menstrual cycle. Outcome measures: The primary outcome measure was the sum of all 21 items in DRSP (Total DRSP score). Secondary outcomes were Negative mood score i.e. the ratings of the 4 key symptoms in PMDD (anger/irritability, depression, anxiety and lability) and impairment (impact on daily life). Results: 26 healthy women completed the pharmacokinetic phase I study and the dosing in the following trial was adjusted according to the results. 106 of the 126 women completed the phase II study. Within this group, a significant treatment effect with UC1010 compared to placebo was obtained for the Total DRSP score (p = 0.041) and borderline significance (p = 0.051) for the sum of Negative mood score. Nineteen participants however showed symptoms during the follicular phase that might be signs of an underlying other conditions, and 27 participants had not received the medication as intended during the symptomatic phase. Hence, to secure that the significant result described above was not due to chance, a post hoc sub-group analysis was performed, including only women with pure PMDD who completed the trial as intended (n = 60). In this group UC1010 reduced Total DRSP scores by 75% compared with 47% following placebo; the effect size 0.7 (p = 0.006), and for sum of Negative mood score (p = 0.003) and impairment (p = 0.010) with the effect size 0.6. No severe adverse events were reported during the treatment and safety parameters (vital signs and blood chemistry) remained normal during the study. Conclusions: This explorative study indicates promising results for UC1010 as a potential treatment for PMDD. The effect size was comparable to that of SSRIs and drospirenone containing oral contraceptives. UC1010 was well tolerated and deemed safe

Pharmacokinetic and behavioral effects of allopregnanolone in healthy women

Rationale  The behavioral effects of allopregnanolone (3α-hydroxy-5α-pregnan-20-one) in women are not known. Objective  Allopregnanolone, a neuroactive steroid secreted by the mammalian ovary, exerts its anesthetic, anxiolytic, and sedative/hypnotic effects through potentiation of GABAA receptors. The purpose of this study was to evaluate the behavioral effects of allopregnanolone in healthy women. Methods  Ten healthy women were given three increasing intravenous doses of allopregnanolone in the follicular phase of the menstrual cycle. Saccadic eye movement parameters and visual analogue scales of sedation were used to evaluate the behavioral response of allopregnanolone. Repeated blood samples for analyses of allopregnanolone were drawn throughout the study day. Results  Exogenously administered allopregnanolone decreases saccadic eye movement parameters and increases subjective ratings of sedation that correlate with increased serum concentrations of this neuroactive steroid. Conclusion  The behavioral effects of allopregnanolone are similar to that of its 5β-stereoisomer, pregnanolone (3α-hydroxy-5β-pregnan-20-one). Apart from fatigue and mild nausea, allopregnanolone given in a cumulative dose of 0.09 mg/kg did not have any adverse effects