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Therapeutics · Hormonal Agents

Pleiotropic actions of allopregnanolone underlie therapeutic benefits in stress-related disease

Boero G, Porcu P, Morrow AL

Published May 2020 Neurobiology of stress, 12, 100203
DOI 10.1016/j.ynstr.2019.100203 PMID 31879693 PMC PMC6920111

Abstract

For several years, research from around the world has suggested that the neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone) may have therapeutic potential for treatment of various stress-related diseases including post-traumatic stress disorder (PTSD), depression, alcohol use disorders (AUDs), as well as neurological and psychiatric conditions that are worsened in the presence of stress, such as multiple sclerosis, schizophrenia, and seizure disorders. In this review, we make the argument that the pleiotropic actions of allopregnanolone account for its ability to promote recovery in such a wide variety of illnesses. Likewise, the allopregnanolone precursors, pregnenolone and progesterone, share many actions of allopregnanolone. Of course, pregnenolone and progesterone lack direct effects on GABAA receptors, but these compounds are converted to allopregnanolone in vivo. This review presents a theoretical framework for understanding how endogenous neurosteroids that regulate 1) γ-aminobutyric acid (GABA)A receptors, 2) corticotropin releasing factor (CRF) and 3) pro-inflammatory signaling in the innate immune system and brain could play a key role in both the prevention and treatment of stress-related disease. We further discuss cautions and limitations of allopregnanolone or precursor therapy as well as the need for more clinical studies.

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By this author

Premenstrual Disorders · Premenstrual Dysphoric Disorder

Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder

Girdler SS et al., 2001 Biol Psychiatry

This study was designed to examine basal and stress-induced levels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic-pituitary-adrenal axis, plasma cortisol levels were examined. An additional goal was to investigate the relationship between premenstrual symptom severity and luteal phase allopregnanolone levels. Twenty-four women meeting prospective criteria for PMDD were compared with 12 controls during both the follicular and luteal phases of confirmed ovulatory cycles, counterbalancing phase at first testing. Plasma allopregnanolone and cortisol were sampled after an extended baseline period and again 17 min following the onset of mental stress. Owing to low follicular phase allopregnanolone levels, only luteal phase allopregnanolone and cortisol were analyzed. During the luteal phase, PMDD women had significantly greater allopregnanolone levels, coupled with significantly lower cortisol levels, during both baseline and mental stress. Moreover, significantly more controls (83%) showed the expected stress-induced increases in allopregnanolone compared with PMDD women (42%). Premenstrual dysphoric disorder women also exhibited a significantly greater allopregnanolone/progesterone ratio than control subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women. No relationship between symptom severity and allopregnanolone was observed in controls. These results suggest dysregulation of allopregnanolone mechanisms in PMDD and that continued investigations into a potential pathophysiologic role of allopregnanolone in PMDD are warranted.

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Hormonal Agents · Progesterone and Progestins

Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence

Prior JC, 2015 Curr Opin Endocrinol Diabetes Obes

Provide evidence-based recent data on oral micronized progesterone (OMP) and progestins in menopausal hormonal therapy (MHT). RECENT Findings: Medroxyprogesterone acetate (MPA) increases breast cancer acting through the glucocorticoid receptor; progestins in MHT increase thrombosis more than oral estrogens; MPA, but not OMP or other progestins, increase monocyte cell endothelium adhesion; MPA and estradiol (E2)/MPA have negative brain effects, whereas E2/progesterone (P4) has neuroregenerative brain effects. The 'window of opportunity' cardiovascular disease hypothesis is not supported by a randomized controlled trial showing that transdermal estradiol with sequential OMP in early menopause does not prevent increased carotid intimal media thickness; P4 in the cardiac electrical system opposes E2 effects and prevents sudden death/long QT syndrome; transdermal estradiol/OMP does not increase venous thromboembolism in observational data. P4 decreases breast cell proliferation and improves prognosis through P4 receptor alteration of estrogen receptor α genetic effects; OMP with conjugated equine estrogen (CEE)/estrogen (E)/E2 does not increase breast cancer in two prospective cohorts, one population-based. Endometrial cancer is increased in MHT of CEE/E/E2+cyclic OMP at 200 mg/day. New data show CEE/E/E2+MPA/P mechanisms for negative breast cancer, venous thromboembolism, cardiovascular system, and brain effects. OMP/P4 counterbalances CEE/E/E2-related negative effects on breast cancer and long QT syndrome. OMP effectively treats vasomotor symptoms and sleep disturbances, and could safely be used alone for symptomatic menopause.

Hormonal Agents · Progesterone and Progestins

Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate

Nilsen J et al., 2001 Endocrinology

Estrogen replacement therapy is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. To compare the impact of therapeutically relevant progestins on estrogen-induced neuroprotection, we treated primary hippocampal neuron cultures with 17beta-E2 and progestin, alone and in combination, 48 h before glutamate insult. Estrogen, progesterone, and 19-norprogesterone, alone or in combination, protected against glutamate toxicity. In contrast, medroxyprogesterone acetate (MPA) failed to protect against glutamate toxicity. Not only was MPA an ineffective neuroprotectant but it attenuated the estrogen- induced neuroprotection when coadministered. We addressed the role of MAPK activation in neuroprotection by ovarian steroids. Estrogen and all three progestins tested, alone or in combination, activated MAPK, indicating another mechanism of protection. Bcl-2 expression has been shown to prevent cell death and is up-regulated by 17beta-E2. Progesterone and 19-norprogesterone, alone or in combination with estrogen, increased Bcl-2 expression. In contrast, MPA blocked estrogen-induced Bcl-2 expression when coadministered. These results may have important implications for the effective use of hormone replacement therapy in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimer's disease.

Premenstrual Disorders · Premenstrual Dysphoric Disorder

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

Hantsoo L et al., 2020 Neurobiology of stress Free full text on PubMed Central

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 GABAA receptor (GABAA-R), in PMDD's pathophysiology. We review evidence of impaired interaction between ALLO and GABAA-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 GABAA-Rs provide evidence for impaired ALLO-GABA function in PMDD. In sum, the literature supports the hypothesis that PMDD pathophysiology is rooted in impaired GABAA-R response to dynamic ALLO fluctuations across the menstrual cycle, manifesting in affective symptoms and poor regulation of physiologic stress response.

Premenstrual Disorders · Cyclical Symptom Patterns

Progesterone metabolite allopregnanolone in women with premenstrual syndrome

Rapkin AJ et al., 1997 Obstet Gynecol

To evaluate the anxiolytic 3alpha-5alpha-reduced progesterone metabolite allopregnanolone in the luteal phase of the menstrual cycle in women with premenstrual syndrome (PMS) and controls. 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. 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. 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.

Therapeutics › Hormonal Agents › Progesterone and Progestins
PMID 31879693 31879693 DOI 10.1016/j.ynstr.2019.100203 10.1016/j.ynstr.2019.100203 Boero et al. 2020, Boero 2020

Cite this article

Boero, G., Porcu, P., & Morrow, A. L. (2020). Pleiotropic actions of allopregnanolone underlie therapeutic benefits in stress-related disease. Neurobiology of stress, 12, 100203. https://doi.org/10.1016/j.ynstr.2019.100203

Keywords

Allopregnanolone, CRF, GABAergic transmission, Pregnenolone, Progesterone, Toll-like receptors

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