Progesterone metabolite allopregnanolone in women with premenstrual syndrome
Objective
To evaluate the anxiolytic 3α-5α-reduced progesterone metabolite allopregnanolone in the luteal phase of the menstrual cycle in women with premenstrual syndrome (PMS) and controls.
Methods
Thirty-five women with prospectively documented PMS and 36 controls were evaluated. Serum progesterone and allopregnanolone levels were measured on days 19 and 26 of the cycle as determined by urinary LH detection kits. Analysis of variance and Student t tests were used to analyze the data.
Results
Allopregnanolone levels were significantly lower on day 26 in the PMS group than in controls (3.6 ± 0.8 versus 7.5 ± 1.3 ng/mL; P < .04). Significant differences in the ratio of the metabolite to progesterone also were noted, with a smaller ratio in the PMS subjects (0.9 ± 0.3 versus 3.2 ± 1.3 ng/mL; P < .05). There were no significant differences between the PMS and control groups with respect to serum progesterone levels.
Conclusion
Subjects with PMS manifested lower levels of the anxiolytic metabolite allopregnanolone in the luteal phase when compared with controls. Diminished concentrations of allopregnanolone in women with PMS may lead to an inability to enhance gamma aminobutyric acid-mediated inhibition during states of altered central nervous system excitability, such as ovulation or physiologic or psychological stress. The lowered metabolite levels could contribute to the genesis of various mood symptoms of the disorder, such as anxiety, tension, and depression.
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Cited by (294)
Premenstrual dysphoric disorder (PMDD): Drug and psychotherapeutique management, a literature review
2024, EncephaleLe trouble dysphorique prémenstruel (TDPM) est reconnu pour la première fois en juillet 2013 dans le DSM-5 après un long parcours pour identifier son existence. Ce n’est qu’en 1983 que l’institut national de la santé mentale américaine détermine des critères de recherche pour l’étude sur le syndrome prémenstruel. En 1994, Le terme « trouble dysphorique prémenstruel » (TDPM) remplace ce terme dans la quatrième édition du Diagnostic System Manuel (DSM), il est inscrit dans la section « Trouble de l’humeur non spécifié » et restera à l’étude jusqu’au DSM-5, dans lequel il apparaîtra dans la section des troubles dépressifs. La légitimation du diagnostic psychiatrique ainsi que la détermination de critères de symptomatologie clairs en 2013 ouvrent sur des possibilités de prises en charge, de développement des études cliniques, physiopathologiques, thérapeutiques et psychothérapeutiques. Ce trouble invalidant peut retentir sur la vie personnelle, sociale, familiale et professionnelle. En 2019, la CIM-11 fait apparaître à son tour le diagnostic de trouble dysphorique prémenstruel, ce qui solidifie la reconnaissance du trouble.
(I) faire le point sur les traitements existants, médicamenteux et psychothérapeutiques, ainsi que (II) faire le point sur leur efficacité. À l’issue de ce travail nous formulerons des recommandations pour les prises en charge de ces patientes.
Une recherche bibliographique a été effectuée du 7 juin 2021 au 7 juillet 2021 sur les bases de données Psychinfo APA, Scopus, PubMed, ainsi que les bases de données de l’organisation Cochrane et les documents de recommandations de la Haute Autorité de la santé. Après une première sélection à partir de mots-clés, une lecture du texte intégral de l’ensemble a été effectuée pour arriver à la sélection finale de 32 articles.
Les antidépresseurs et les thérapies cognitivo-comportementales (TCC) apparaissent comme les traitements majoritairement recommandés dans la prise en charge du TDPM. D’autres recherches montrent l’efficacité des contraceptifs oraux comprenant de la drospirénone. On identifie les inhibiteurs sélectifs de la recapture de sérotonine (ISRS) comme étant un traitement efficace du TDPM. Ces données vont dans le sens de l’hypothèse étiologique actuelle du TDPM qui est un impact négatif des fluctuations hormonales naturelles sur certains neurotransmetteurs. Les TCC montrent des résultats positifs pour réduire l’impact fonctionnel du TDPM.
Les antidépresseurs de type inhibiteur sélectif de la recapture de la sérotonine (ISRS) seraient les traitements de première intention du TDPM (sertraline 50–150 mg/j, la fluoxétine 10–20 mg/j, l’escitalopram 10–20 mg/j, la paroxétine 12,5–25 mg par jour/j). La drospirénone (EE 3 mg et EE 20 mg/j 24 jours de pilules hormonales, 4 jours inactifs) apparaît comme un traitement de première intention ou de deuxième intention en fonction des articles. Les résultats actuels vont clairement dans le sens d’une efficacité de la TCC pour contribuer à réduire : l’atteinte fonctionnelle, l’humeur dépressive, le sentiment de désespoir, l’anxiété, les sauts d’humeur, la sensibilité, l’irritabilité, l’insomnie, les conflits avec les autres, l’impact des symptômes prémenstruels sur la vie quotidienne, l’intensité des symptômes ressentis et le handicap des symptômes. Les TCC pourraient également apparaître dans les traitements de première intention si les preuves de leur efficacité étaient plus nombreuses. Dans l’avenir, il semble utile de proposer une prise en charge psychothérapique qui puisse être reproductible et de multiplier les recherches d’un haut niveau de comparabilité scientifique afin de clarifier la place des TCC dans la prise en charge du TDPM. Les recherches sur l’étiopathologie du trouble et le schéma thérapeutique médicamenteux optimal sont encore en cours. Il est nécessaire de développer des techniques psychothérapeutiques adaptées afin de soutenir et d’accompagner ces patientes.
Pour permettre une meilleure évaluation des traitements du TDPM, l’homogénéisation des études sur le sujet est nécessaire à plusieurs niveaux : design, doses de traitements, techniques psychothérapeutiques, et mesures d’évaluation. À l’heure actuelle, certaines études portent à la fois sur des patientes qui souffrent de syndrome prémenstruel (SPM) et sur des patientes qui souffrent de TDPM. Le SPM et le TDPM n’incluent pas les mêmes symptômes, ni la même sévérité et potentiellement pas la même étiologie chez les patientes étudiées. Afin de proposer des recherches rigoureuses qui évaluent l’efficacité des traitements sur le TDPM et d’accompagner correctement les personnes atteintes de ces troubles, il semble essentiel de bien distinguer les deux pathologies. Le rôle du praticien de santé est de savoir identifier le TDPM en le différenciant d’autres troubles cliniquement proches. La patiente doit ensuite être accompagnée pour faire un choix de traitement adapté en fonction des symptômes, de leur sévérité, des antécédents, de ses projets de procréation, des contre-indications et de ses préférences. En 2021, la Haute Autorité de la Santé ne propose aucun guide ou recommandation pour la gestion du trouble dysphorique prémenstruel. Il est nécessaire de développer les recherches en France.
Premenstrual Dysphoric Disorder (PMDD) was first recognised in July 2013 in the DSM-5 after a long journey to identify its existence. It was not until 1983 that the US National Institute of Mental Health determined research criteria for the study of PMS. In 1994, the term “premenstrual dysphoric disorder” (PMDD) replaced this term in the 4th edition of the Diagnostic System Manual (DSM). It was listed in the section “Mood Disorder Not Otherwise Specified” and remained under consideration until the DSM-5, in which it appeared in the depressive disorders section. The legitimisation of the psychiatric diagnosis as well as the determination of clear symptomatology criteria in 2013 opened up possibilities for management, development of clinical, pathophysiological, therapeutic and psychotherapeutic studies. This disabling disorder can affect personal, social, family and professional life. In 2019, the ICD-11 in turn introduced the diagnosis of premenstrual dysphoric disorder, which solidifies the recognition of the disorder.
(I) to review the existing treatments, both medicinal and psychotherapeutic, and (II) to review their effectiveness. At the end of this work we will formulate recommendations for the management of these patients.
A bibliographic search was carried out from 7 June 2021 to 7 July2021 on the databases (bases de données) Psychinfo APA, Scopus, PubMed, as well as the bases de données of the Cochrane organisation and the recommendation documents of the Haute Autorité de la santé. After an initial selection based on keywords, the full text of all articles were read to arrive at the final selection of 32 articles.
Antidepressants and Cognitive Behavioural Therapies (CBT) appear to be the most commonly recommended treatments for PMDD. Other research shows the effectiveness of oral contraceptives including drospirenone. Selective serotonin reuptake inhibitors (SSRIs) were identified as an effective treatment for PMDD. These data are consistent with the current etiological hypothesis of PMDD which has a negative impact of natural hormonal fluctuations on certain neurotransmitters. CBT showed positive results in reducing the functional impact of PMDD.
Selective serotonin reuptake inhibitor (SSRI) antidepressants were reported to be first-line treatments for PMDD (sertraline 50–150 mg/d, fluoxetine 10–20 mg/d, escitalopram 10–20 mg/d, paroxetine 12.5–25 mg/d). Drospirenone (EE 3 mg and EE 20 mg/d 24 days of hormonal pills, 4 days inactive) appears to have been a first or second line treatment depending on the articles. Current results clearly point to the effectiveness of CBT in helping to reduce: functional impairment, depressed mood, feelings of hopelessness, anxiety, mood swings, sensitivity, irritability, insomnia, conflict with others, impact of premenstrual symptoms on daily life, intensity of symptoms experienced, and symptom handicap. CBTs could also become a first-line treatment if there were to be more evidence of their effectiveness. In the future, it would seem useful to offer a psychotherapeutic treatment that can be reproduced and to multiply research with a high level of scientific comparability in order to clarify the place of CBT in the management of PMDD. Research on the etiopathology of the disorder and the optimal drug regimen is still ongoing. There is a need to develop appropriate psychotherapeutic techniques to support and accompany these patients.
In order to better evaluate treatments for PMDD, there is a need to homogenise studies on the subject at several levels: design, treatment doses, psychotherapeutic techniques, and evaluation measures. At present, some studies include both premenstrual syndrome (PMS) and PMDD patients. PMS and PMDD do not include the same symptoms, nor the same severity and potentially the same aetiology in the patients studied. In order to propose rigorous research that evaluates the effectiveness of treatments for PMDD and to properly support people with both these disorders, it seems essential to distinguish the two conditions. The role of the health practitioner is to be able to identify PMDD by differentiating it from other clinically related disorders. The patient must then be accompanied to make a choice of treatment adapted to her symptoms, their severity, her history, her plans for procreation, contraindications and her preferences. In 2021, the French National Authority for Health did not offer any guidelines or recommendations for the management of premenstrual dysphoric disorder. There is a need to develop research in France.
GABAergic neuroactive steroid response to sertraline in premenstrual dysphoric disorder
2024, PsychoneuroendocrinologyPremenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD’s pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD.
The aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms.
Participants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5β-THP; pregnenolone; 3α,5α-androsterone; 3α,5β-androsterone; 3α,5α-A-diol; 3α5β-A-diol; 3α,5α-THDOC; 3α5β-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment.
Participants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone.
This was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design.
Reduced urine pregnenolone concentration after clinical response in patients with depression: An open-label short-term prospective study
2023, PsychoneuroendocrinologyIdentifying biological alterations in patients with depression, particularly those that differ between responders and non-responders, is of interest to clinical practice. Biomarker candidates involve neuroactive steroids, including pregnenolone (PREG) and allopregnanolone (ALLO). However, alterations in PREG and ALLO associated with treatment response are understudied. This study's main aim was to evaluate the effects of antidepressant treatment, clinical response, and treatment duration on PREG and ALLO in depression.
In a 4-week, open-label trial, participants were allocated randomly to the venlafaxine (n = 27) or mirtazapine (n = 30) group. Urine concentrations of PREG and ALLO were assessed through gas chromatography-mass spectrometry. Participants collected night urine between 10:30 p.m. and 8:00 a.m. Two primary outcomes were analyzed. Firstly, the effect of treatment (mirtazapine or venlafaxine), clinical response (operationalized through the Hamilton Depression Rating Scale), and time (baseline compared to 28 days) on the urine concentrations of PREG or ALLO in depression. Finally, the effect of clinical response and time on the urine concentration of PREG or ALLO, independently of the antidepressant given (mirtazapine or venlafaxine). Linear mixed models were carried out.
There was no significant difference in PREG and ALLO concentrations between baseline and 28 days in responders and non-responders when investigating the venlafaxine or the mirtazapine group. However, we found a significant reduction of urine PREG concentration after 28 days of treatment in responders who received either venlafaxine or mirtazapine (estimate = −0.56; p = 0.016; 95CI [−1.003; −0.115]; Cohen’s d = −0.61).
Our main results indicate that responders in depression show reduced urinary PREG concentrations after 4-weeks of therapy, independently of the antidepressant used. More studies are needed to confirm these findings.
Towards understanding the biology of premenstrual dysphoric disorder: From genes to GABA
2023, Neuroscience and Biobehavioral ReviewsPremenstrual dysphoric disorder (PMDD) is a severe mood disorder, with affective symptoms that rise and fall in concert with the hormonal fluctuations of the menstrual cycle. PMDD’s pathophysiology is poorly understood. This review describes recent research on potential biological contributors to PMDD, with a focus on neuroactive steroids, genetics, neuroimaging and cellular studies. Studies suggest that a key contributor is abnormal central nervous system (CNS) response to fluctuations in neuroactive steroid hormones. Imaging studies are limited but support alterations in serotonergic and GABA transmission. Genetic studies suggest heritability, yet specific genetic contributors have not been characterized. Finally, recent cutting-edge cellular studies indicate an underlying vulnerability to the effect of sex hormones at a cellular level. Overall the findings across studies do not yet fit together into a complete description of the underlying biology of PMDD. It is possible that PMDD consists of biological subtypes, and future research may benefit from a subtyping approach.
Can animal models resemble a premenstrual dysphoric condition?
2022, Frontiers in NeuroendocrinologyAround 80% of women worldwide suffer mild Premenstrual Disorders (PMD) during their reproductive life. Up to a quarter are affected by moderate to severe symptoms, and between 3% and 8% experience a severe form. It is classified as premenstrual syndrome (PMS) with predominantly physical symptoms and premenstrual dysphoric disorder (PMDD) with psychiatric symptoms. The present review analyzes the factors associated with PMD and the Hypothalamus-Pituitary-Ovarian or Hypothalamus-Pituitary-adrenal axis and discusses the main animal models used to study PMDD. Evidence shows that the ovarian hormones participate in PMDD symptoms, and several points of regulation of their synthesis, metabolism, and target sites could be altered. PMDD is complex and implies several factors that require consideration when this condition is modeled in animals. Of particular interest are those points related to areas that may represent opportunities to develop new approximations to understand the mechanisms involved in PMDD and possible treatments.
Premenstrual syndrome and premenstrual dysphoric disorder in adolescents
2022, Current Problems in Pediatric and Adolescent Health CarePremenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) represent two premenstrual disorders characterized by physical and psychological symptoms that occur in the luteal phase of the menstrual cycle, prior to the onset of menses, and have a negative impact on the psychosocial functioning of affected individuals. PMS, more common than PMDD, affects 20-40% of menstruating women, with common symptoms including fatigue, irritability, mood swings, depression, abdominal bloating, breast tenderness, acne, changes in appetite and food cravings. PMDD, affecting a smaller percentage of women, is characterized by more severe symptoms and is listed as a depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). While the pathophysiology of these premenstrual disorders remains unclear, it has been hypothesized that sensitivity to hormonal fluctuations during the luteal phase of the menstrual cycle, abnormal serotonergic activity, and aberrations in progesterone and the neurotransmitter gamma aminobutyric acid (GABA) may all play a role in these disorders. Treatment of PMS and PMDD is focused on alleviation of symptoms and improvement of functioning and quality of life for affected individuals. The treatment of severe PMS and PMDD typically requires pharmacologic therapy with selective serotonin reuptake inhibitors (SSRIs), oral contraceptive pills (OCPs), gonadotropin-releasing hormone (GnRH) agonists, and non-contraceptive estrogen formulations. Non-pharmacologic treatment with diet, exercise, cognitive behavioral therapy (CBT), certain vitamin and herbal supplements, and acupuncture may additionally be effective for some individuals.