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      Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle


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          Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with core symptoms (affective lability, irritability, depressed mood, anxiety) and increased sensitivity to stress occurring in the luteal phase of the menstrual cycle. PMDD can be conceptualized as a disorder of suboptimal sensitivity to neuroactive steroid hormones (NASs). In this review, we describe the role of the NAS allopregnanolone (ALLO), a positive allosteric modulator of the GABA A receptor (GABA A-R), in PMDD's pathophysiology. We review evidence of impaired interaction between ALLO and GABA A-Rs in terms of affective symptom expression, with evidence from rodent and human studies. We discuss evidence of increased luteal phase stress sensitivity as a result of poor ALLO-GABA control of the HPA axis. Finally, we describe how treatments such as selective serotonin reuptake inhibitors (SSRIs) and new drugs targeting GABA A-Rs provide evidence for impaired ALLO-GABA function in PMDD. In sum, the literature supports the hypothesis that PMDD pathophysiology is rooted in impaired GABA A-R response to dynamic ALLO fluctuations across the menstrual cycle, manifesting in affective symptoms and poor regulation of physiologic stress response.

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          Most cited references104

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          Sex differences in anxiety and depression clinical perspectives.

          Sex differences are prominent in mood and anxiety disorders and may provide a window into mechanisms of onset and maintenance of affective disturbances in both men and women. With the plethora of sex differences in brain structure, function, and stress responsivity, as well as differences in exposure to reproductive hormones, social expectations and experiences, the challenge is to understand which sex differences are relevant to affective illness. This review will focus on clinical aspects of sex differences in affective disorders including the emergence of sex differences across developmental stages and the impact of reproductive events. Biological, cultural, and experiential factors that may underlie sex differences in the phenomenology of mood and anxiety disorders are discussed.
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            Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity.

            Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation. From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis. The HPA axis influences many physiological functions making an organism's response to changes in the environment appropriate for its reproductive status. Although the acute HPA response to stressors is a beneficial response, constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology. Compared to males, female mice and rats show a more robust HPA axis response, as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors. Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males. Moreover, gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty. Correspondingly, crosstalk between the hypothalamic-pituitary-gonadal (HPG) and HPA axes could lead to abnormalities of stress responses. In humans, a dysregulated stress response is one of the most common symptoms seen across many neuropsychiatric disorders, and as a result, such interactions may exacerbate peripheral pathologies. In this review, we discuss the HPA and HPG axes and review how gonadal steroids interact with the HPA axis to regulate the stress circuitry during all stages in life.
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              Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety.

              Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by delta subunit-containing GABA(A) receptors (deltaGABA(A)Rs). Here we demonstrate periodic alterations in specific GABA(A)R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of deltaGABA(A)Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of deltaGABA(A)Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of deltaGABA(A)Rs in individuals with catamenial epilepsy or PMDD.

                Author and article information

                Neurobiol Stress
                Neurobiol Stress
                Neurobiology of Stress
                04 February 2020
                May 2020
                04 February 2020
                : 12
                : 100213
                [a ]Department of Psychiatry & Behavioral Sciences, The Johns Hopkins University School of Medicine, 550 N, Broadway Street Baltimore, MD, 21205, USA
                [b ]Department of Psychiatry, University of Colorado School of Medicine Anschutz Medical Campus, 13001 E 17th Place, MS F546, Aurora, CO, 80045, USA
                Author notes
                []Corresponding author. LHantso1@ 123456jhmi.edu
                S2352-2895(20)30003-5 100213
                © 2020 Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 2 December 2019
                : 24 January 2020
                : 31 January 2020
                Articles from the Special Issue on Allopregnanolone role in the neurobiology of stress and mood disorders; Edited by Graziano Pinna

                menstrual cycle,premenstrual dysphoric disorder,premenstrual syndrome,allopregnanolone,progesterone,women's health


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