| 1. |
- Bixo, Marie, et al.
(författare)
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Treatment of premenstrual dysphoric disorder with the GABA(A) receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial
- 2017
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Ingår i: Psychoneuroendocrinology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0306-4530 .- 1873-3360. ; 80, s. 46-55
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Tidskriftsartikel (refereegranskat)abstract
- Context: Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABA(A) 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 GABA(A) 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.
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| 4. |
- Bäckström, Torbjörn, et al.
(författare)
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A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder
- 2021
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 133
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Tidskriftsartikel (refereegranskat)abstract
- Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABAA receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21 <42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020). The results indicate that there is an attenuating effect by sepranolone on symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. Sepranolone was well tolerated, and no safety concerns were identified.
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| 5. |
- Cardinale, Daniele A., 1982-, et al.
(författare)
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Enhanced Skeletal Muscle Oxidative Capacity and Capillary-to-Fiber Ratio Following Moderately Increased Testosterone Exposure in Young Healthy Women
- 2020
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Ingår i: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recently, it was shown that exogenously administered testosterone enhances endurance capacity in women. In this study, our understanding on the effects of exogenous testosterone on key determinants of oxygen transport and utilization in skeletal muscle is expanded.Methods: In a double-blinded, randomized, placebo-controlled trial, 48 healthy active women were randomized to 10 weeks of daily application of 10 mg of testosterone cream or placebo. Before and after the intervention, VO2 max, body composition, total hemoglobin (Hb) mass and blood volumes were assessed. Biopsies from the vastus lateralis muscle were obtained before and after the intervention to assess mitochondrial protein abundance, capillary density, capillary-to-fiber (C/F) ratio, and skeletal muscle oxidative capacity.Results: Maximal oxygen consumption per muscle mass, Hb mass, blood, plasma and red blood cell volumes, capillary density, and the abundance of mitochondrial protein levels (i.e., citrate synthase, complexes I, II, III, IV-subunit 2, IV-subunit 4, and V) were unchanged by the intervention. However, the C/F ratio, specific mitochondrial respiratory flux activating complex I and linked complex I and II, uncoupled respiration and electron transport system capacity, but not leak respiration or fat respiration, were significantly increased following testosterone administration compared to placebo.Conclusion: This study provides novel insights into physiological actions of increased testosterone exposure on key determinants of oxygen diffusion and utilization in skeletal muscle of women. Our findings show that higher skeletal muscle oxidative capacity coupled to higher C/F ratio could be major contributing factors that improve endurance performance following moderately increased testosterone exposure.
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| 6. |
- Ekenros, Linda, et al.
(författare)
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Changes in premenstrual symptoms in women starting or discontinuing use of oral contraceptives
- 2019
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Ingår i: Gynecological Endocrinology. - : Taylor & Francis Group. - 0951-3590 .- 1473-0766. ; 35:5, s. 422-426
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Tidskriftsartikel (refereegranskat)abstract
- It is not clear whether oral contraceptive (OC) treatment affects premenstrual symptoms in women. The aim of the present study was to evaluate changes in premenstrual symptoms (PMS) in women starting to use or discontinuing the use of OCs. Twenty-four healthy women with no previous diagnosis of premenstrual dysphoric disorder were included in this study with a prospective crossover design. Nineteen women completed daily ratings of somatic and mood symptoms during two hormonally different cycles, during a normal menstrual cycle and while using OCs. The menstrual cycle phases were hormonally verified and the low-dose, monophasic OCs were used in a 21/7 regimen. The onset of OC use significantly decreased premenstrual somatic symptoms, but it did not affect mood symptoms. In the women who discontinued OC use, no significant changes in neither somatic nor mood symptoms appeared in the premenstrual phase.
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| 7. |
- Ekenros, Linda, et al.
(författare)
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Impact of Menstrual cycle-based Periodized training on Aerobic performance, a Clinical Trial study protocol—the IMPACT study
- 2024
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Ingår i: Trials. - : BioMed Central (BMC). - 1745-6215. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The menstrual cycle and its impact on training and performance are of growing interest. However, evidence is lacking whether periodized exercise based on the menstrual cycle is beneficial. The primary purpose of this proposed randomized, controlled trial, the IMPACT study, is to evaluate the effect of exercise periodization during different phases of the menstrual cycle, i.e., comparing follicular phase-based and luteal phase-based training with regular training during the menstrual cycle on physical performance in well-trained women.Methods: Healthy, well-trained, eumenorrheic women between 18 and 35 years (n = 120) will be recruited and first assessed for physical performance during a run-in menstrual cycle at different cycle phases and then randomized to three different interventions: follicular phase-based training, luteal phase-based training, or regular training during three menstrual cycles. The training intervention will consist of high-intensity spinning classes followed by strength training. The menstrual cycle phases will be determined by serum hormone analysis throughout the intervention period. Assessment of aerobic performance (primary outcome) and muscle strength, body composition, and blood markers will be performed at baseline and at the end of the intervention.Discussion: With a robust methodology, this study has the potential to provide evidence of the differential effects of exercise periodization during different phases of the menstrual cycle in female athletes.Trial registration: ClinicalTrials.gov NCT05697263 . Registered on 25 January 2023
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| 8. |
- Ekenros, Linda, et al.
(författare)
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Perceived impact of the menstrual cycle and hormonal contraceptives on physical exercise and performance in 1,086 athletes from 57 sports
- 2022
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Ingår i: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Female athletes train and compete under the potential influence of hormonal fluctuations during the menstrual cycle or during use of various hormonal contraceptives. Dysmenorrhea and premenstrual symptoms are common in the general population, as well as side effects of hormonal contraceptives. More detailed knowledge concerning prevalence and perceived impact of these symptoms on training and performance in different sports is required. The aim of the study was to 1) characterize perceptions of training and performance during the menstrual cycle phases and by hormonal contraceptive use in a large population of female athletes; 2) explore whether symptoms experienced are related to perceived performance; and 3) examine potential differences in these factors between athletes at different levels of performance. The study was based on self-reported data from 1,086 athletes from 57 sports at different performance levels via a web-based questionnaire. Thirty-seven percent (n = 407) of the athletes did not use hormonal contraceptives. In this group, menstrual cycle related symptoms were common across all athlete levels, particularly dysmenorrhea (74%, n = 300) and premenstrual symptoms (78%, n = 318), which also influenced perceived performance of aerobic fitness, muscle strength, mental sharpness, balance, and sleep quality. Sixty-three percent (n = 679) of the athletes used various hormonal contraceptives and 40% (n = 272) perceived a variety of side-effects. Physical performance was experienced equally independent of time-point of the pill-chart except for the period of inactive pills, which was associated with more negative impact. Nonetheless, only 18% (n = 191) of the athletes considered menstrual cycle or hormonal contraceptive issues when planning their training or competitions. These results indicate that greater focus is needed to identify and effectively treat different menstrual cycle and hormonal contraceptive related symptoms on an individual level.
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| 9. |
- Ekenros, Linda, et al.
(författare)
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Postural control in women with premenstrual symptoms during oral contraceptive treatment
- 2011
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 90:1, s. 97-102
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Tidskriftsartikel (refereegranskat)abstract
- Objective. This study investigates postural control among women with and without premenstrual symptoms (PMS) on oral contraceptive (OC) treatment. Design. Prospective repeated measures design. Setting. Women's health clinical research unit at a university hospital. Population. Fifteen women using low-dose monophasic oral contraceptives participated in the study. Depending on premenstrual symptoms, the women were divided into one PMS group and one non-PMS group. Methods. Postural control (displacement area) was measured using an AMTI® force platform during the active hormone phase (OC phase) and the hormone-free phase (non-OC phase) of the pill chart. Premenstrual symptoms were evaluated prospectively using the Cyclicity Diagnoser. Main Outcome Measures. Displacement area as a measure of postural control. Results. Six of 15 women showed premenstrual symptoms (primarily negative mood symptoms) between the phases and were considered having premenstrual symptoms. When analyzing postural control, the PMS group displayed a significantly greater displacement area in the OC-phase compared to the non-OC phase. In contrast, the non-PMS group did not show any significant difference between the phases. Furthermore, the PMS group had significantly greater displacement area during the OC phase compared to the non-PMS group. Conclusions. The present study shows that women with premenstrual symptoms have greater displacement area than those without premenstrual symptoms during the active phase of oral contraceptive treatment. Negative mood symptoms may affect the maintenance of postural control by central interactions. Further studies are needed to clarify the precise mechanism for altered postural control in women with premenstrual symptoms.
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| 10. |
- Engberg, Hedvig, et al.
(författare)
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Congenital adrenal hyperplasia and risk for psychiatric disorders in girls and women born between 1915 and 2010: A total population study.
- 2015
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 60, s. 195-205
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Tidskriftsartikel (refereegranskat)abstract
- Congenital adrenal hyperplasia (CAH) is a chronic condition and individuals are exposed to elevated androgen levels in utero as a result of the endogenous cortisol deficiency. Prenatal androgen exposure has been suggested to influence mental health, but population based studies on psychiatric morbidity among girls and women with CAH are lacking. Therefore, we performed a cohort study based on Swedish nationwide registers linked with the national CAH register. Girls and women with CAH due to 21-hydroxylase deficiency (n=335) born between January 1915 and January 2010 were compared with aged-matched female (n=33500) and male controls (n=33500). Analyses were stratified by phenotype [salt wasting (SW), simple virilizing (SV), and non-classical type (NC)] and by CYP21A2 genotype subgroups (null, I2splice, I172N, and P30L). Results are presented as estimated risks (OR, 95%CI) of psychiatric disorders among girls and women with CAH compared with age-matched controls. Any psychiatric diagnoses were more common in CAH females compared with female and male population controls [1.9 (1.4-2.5), and 2.2 (1.7-2.9)]. In particular, the risk of alcohol misuse was increased compared with female and male population controls [2.8 (1.7-4.7) and 2.1 (1.2-3.5)], and appeared most common among the girls and women with the most severe null genotype [6.7 (2.6-17.8)]. The risk of stress and adjustment disorders was doubled compared with female population controls [2.1 (1.3-3.6)]. Girls and women with CAH have an increased risk of psychiatric disorders in general and substance use disorders in particular compared with unexposed females, with the highest risk among those with the most severe genotype. Prenatal androgen exposure and deficient endogenous cortisol and/or adrenaline production may provide explanations for these findings, but other factors related to CAH cannot be excluded.
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