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Cover page of the Journal of Health Sciences


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 14  |  Issue : 1  |  Page : 137-140

Serum levels of allopregnanolone in migraine patients: A case–control study


1 Department of Emergency Medicine, Isparta State Hospital, Isparta, Turkey
2 Department of Emergency Medicine, Süleyman Demirel University Faculty of Medicine, Isparta, Turkey
3 Department of Emergency Medicine, Health Science University Antalya Training and Research Hospital, Antalya, Turkey

Date of Submission03-Mar-2020
Date of Acceptance15-Oct-2020
Date of Web Publication09-Feb-2021

Correspondence Address:
Dr. Cihan Bedel
Health Science University Antalya Training and Research Hospital, Kazim Karabekir Street, Postal Zip Code: 07100, Muratpaşa, Antalya
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kleuhsj.kleuhsj_52_20

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  Abstract 

Introduction: Migraine is a very common disorder and the mechanisms contributing to headache still remain controversial. Allopregnanolone (AP) is a neurosteroid metabolite of progesterone. Previously, there were some studies of AP on the positive effects of many diseases.
Objectives: The aim of this study was to evaluate AP levels in patients with migraine and compare with levels measured in healthy individuals.
Materials and Methods: This case–control study included fifty patients with acute migraine headache who were previously diagnosed with migraine and fifty sex- and age-matched healthy volunteers with no headache complaints. Migraine patients who fulfilled the International Headache Classification criteria of migraine and healthy controls were included in this study. Plasma AP levels were compared in both groups.
Results: Fifty patients (35 females and 15 males) and fifty healthy volunteers (38 females and 12 males) fulfilled the inclusion criteria and were enrolled in the study. AP levels of migraine patients and control group were compared; there was a statistically significant difference between the two groups (1.22 ± 1.92, 6.07 ± 4.89, respectively; P < 0.001). AP levels were significantly higher in healthy people.
Conclusion: This study showed that low AP levels were detected in migraine patients. These markers may contribute to our understanding of the pathophysiology of migraine.

Keywords: Allopregnanolone, headache, migraine


How to cite this article:
Delikanli M, Beceren NG, Bedel C, Korkut M, Armağan HH. Serum levels of allopregnanolone in migraine patients: A case–control study. Indian J Health Sci Biomed Res 2021;14:137-40

How to cite this URL:
Delikanli M, Beceren NG, Bedel C, Korkut M, Armağan HH. Serum levels of allopregnanolone in migraine patients: A case–control study. Indian J Health Sci Biomed Res [serial online] 2021 [cited 2021 Feb 26];14:137-40. Available from: https://www.ijournalhs.org/text.asp?2021/14/1/137/308967




  Introduction Top


Migraine is a widespread disease in emergency departments (ED), which is characterized by unilateral, throbbing headaches with moderate or severe intensity, and can affect the quality of life. Nausea, vomiting, anorexia, and lightheadedness are some of the most common associated signs and symptoms.[1],[2] It is the third to most common disorder with a worldwide prevalence of 14.7%.[3],[4],[5] Because of its high prevalence and destructive nature, the mechanisms contributing to migraine headaches have been extensively studied for years. However, there is still a debate on this issue.

Allopregnanolone (AP) is a neurosteroid metabolite of progesterone. It is well known that it is an allosteric modulator of inhibitory γ-aminobutyric acid (GABA-A) receptors on neural AP with positive effects on Alzheimer's disease, depression, sleep, posttraumatic stress disorder, and organic brain diseases such as epilepsy.[4],[5],[6] We hypothesized that AP can be associated with migraine patients. Thus, the aim of this study was to evaluate AP levels in patients with migraine and compare with levels measured in healthy individuals.


  Materials and Methods Top


A retrospective case–control study was conducted. Study reporting was done according to the STROBE criteria.[6] Ethical permit for conducting the study was obtained from the Suleyman Demirel Univsersity Institutional Ethical Committee with Ref no 2016/122 dated 21.07.2016 and conducted at the same university hospital ED from October 2016 to January 2017. The Helsinki Declaration was followed during all study processes. All of the participants were volunteers. All the participants read and signed the informed consent form. In this case–control study, a ratio of 1:1 is recommended. A total of fifty patients were included in the study. The study population consisted of fifty patients with acute migraine headache who were previously diagnosed with migraine and fifty sex- and age-matched healthy volunteers with no headache complaints. The inclusion criterion for migraine patients was the diagnosis of migraine according to the International Classification of Headache Disorders III (beta version).[2] Patients with migraine headache (with or without aura), in the 18–60 age range, aware of the disease, and experienced at least one migraine attack in the last 3 months were included in the study. Patients who did not volunteer, were pregnant or suspected that they were pregnant, were in the lactation period, had a history of serious medical problems (heart, liver, and kidney disease, diabetes, and depression), had concurrent treatment (herbal or chemical medicine), had abnormal neurologic findings, or head trauma within the last month were excluded from this study. The diagnosis of migraine and evaluation of inclusion and exclusion criteria were performed by the same physician.

According to the IHS classification, the patients with migraine were divided into two subgroups: migraine with or without aura. The demographic characteristics of the patients, family history, the type and features of pain (pulsating or others), factors associated with pain, and the relationship between pain and menstrual cycle were examined. Patients were divided into age groups as follows: 18–29; 30–39; 40–49; and 50–60. Patients were randomly assigned to age groups. The duration of the disease is defined as < 1 year, 1–5 years, 6–10 years, and more than 10 years. Blood samples were collected before any treatment was administered to the patient from both groups and placed into empty tubes. First, serum samples were centrifuged at 4000 rpm for 5 min, and then the samples were stored immediately at -20°C. Serum samples (1 mL) were thawed. Eight tubes were centrifuged for a standard sample. A 20 ng/mL solution was generated by dilution and serial dilutions were made for each tube (20, 10, 5, 2.5, 1.25, 0.625, 0.313, and 0 ng/mL) as compared to the previous one. The undiluted standard was considered to function as the highest standard (20 ng/mL), functioning as the reference standard, and sample diluent 0 ng/mL. Fifty microliters of the standard was added into each tube. Biotinylated detection antibodies were centrifuged and diluted. Fifty microliters biotinylated detection was added to each tube. The obtained samples were incubated at 37°C for 45 min, and the samples were washed three times. Horseradish peroxidase was diluted, and 100 μl of each vial was added. The obtained samples were incubated at 37°C for 30 min, and the samples were washed five times. About 100 μl substrate mixture solution was added into each tube. Obtained samples were incubated at 37°C for 5 min. The solution was read immediately after the reaction, and the results were obtained.

The data analysis was conducted using IBM Statistical Package for the Social Sciences (SPSS) Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were applied for the relevant parameters. In situations where parametric test assumptions were made, Student's t-test was used for the difference between the two independent groups, and the Chi-square test was used for categorical data. Furthermore, in the case of a relation between continuous variables, “Spearman correlation coefficients” were used. P < 0.05 was considered to be statistically significant.


  Results Top


During 3 months, fifty patients (35 females and 15 males) and fifty healthy volunteers (38 females and 12 males) fulfilled the inclusion criteria and were enrolled in the study. The mean age of the patients was 35.5 ± 12.11 years. According to the age distribution, four groups were formed: 18–29 years old (n = 21), 30–39 years old (n = 9), 40–49 years old (n = 14), and 50–60 years old (n = 6). Thirty-one (62%) of the patients had no family history, whereas 19 (38%) had a family history. In the assessment of headache frequency, seven (14%) patients had migraine headaches several times a year, 22 (44%) had 2–3 times a month, 16 (32%) had more than 2–3 times per week, and 5 (10%) had pain every day. According to the IHS classification, migraine patients were divided into two groups with or without auras, and 18 (36%) of them were classified as migraine without aura, and 32 (64%) were classified as migraine with aura. The demographic distribution of subgroups and symptoms associated with pain are shown in [Table 1].
Table 1: Baseline characteristics of patients

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When the AP levels of migraine patients and control group were compared, there was a statistically significant difference between two groups (1.22 ± 1.92, 6.07 ± 4.89, respectively; P < 0.001). AP levels were significantly higher in healthy people [Table 2]. There was a moderate negative correlation between migraine and AP level (r = -0.576; P < 0.001). The distribution of AP levels according to sex is shown in [Table 2] and [Figure 1]. The relationship of AP level with the menstrual cycle, aura, or family history is shown in [Table 2].
Table 2: Comparison of allopregnanolone levels between groups

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Figure 1: Distribution of AP levels in gender AP: Allopregnanolone levels Patients blue: Male (0.817 ng/ml); patient red: Female (1.198 ng/ml) Control blue: Male (6.202 ng/ml); control red: Female (5.992 ng/ml)

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  Discussion Top


Migraine is a common, chronic neurovascular disease that has a significant effect on the quality of life. It affects up to 10% of the world's population, and every year, more than one million patients present to EDs due to this disease.[7] According to our national data, the prevalence of migraine is about 9% for men and 25% for female. It was found to be higher in females aged 35–40 than in other age groups and males.[8] In our study, similar demographic data were obtained, but the sociocultural characteristics of the studied region and the selection of the sample may show variation.

The study of 40 women with menstrual-related migraine by MacGregor et al. concluded that migraine attack might be associated with a sudden drop in estrogen hormone during the late luteal or early follicular phase of the menstrual cycle, and there was no relationship between progesterone levels and migraine exposure.[9] Hossain et al. found that in the premenstrual period, headache increased in the first 2 days of the cycle, indicating that the reduction in estrogen level was a triggering factor for attacks.[10] Although AP, which is the basis of the study, has not been statistically related to menstruation, it has neuroprotective properties in serotoninergic and opioid receptors; so, prospective research is needed about this topic.

Our study showed that when the AP levels decreased, the incidence of migraine increased. AP is a progesterone metabolite. The incidence of migraine increases when the progesterone level is lower. It is not exactly clear which mechanism it affects. Chiapponi et al. have reported that GABA levels are reduced in migraine, stress, depression, and addiction.[11] AP is an allosteric modulator of inhibitory GABA-A receptors on neural stem cells and other cell types in the brain, so progesterone might also be effective on migraine through GABA.

Ishikawa et al. reported that AP was found to increase neurogenesis, reduce amyloid deposition, and improve the performance of learning and memory tests in mouse models of Alzheimer's disease.[12] It was stated that AP has a low molecular weight, can easily pass through the blood–brain barrier, and reduce toxicity and thus may be a key role in the treatment of Alzheimer's disease.

Naylor et al. found that AP levels are lower in those with chronic muscle pain.[13] Perkins et al. showed that in anxiety disorders patients, AP levels were low, which leads to decrease in the level of GABAergic neurons and is the basis of the pathophysiology of anxiety disorders.[14] Joshi and Kapur observed that the therapeutic use of resistant epilepsy by increasing the AP level was beneficial.[15] In another study, the authors found that depressive symptoms were associated with low progesterone metabolism in ovariectomized rats.[16] Sergeeva et al. suggested the therapeutic potential of AP for the modulation of plasticity in certain eye and brain disorders.[17] In a recent study, researchers found that AP may play an essential role in dynamically modulating vagal inhibition in models of disease.[18] In vitro and in vivo analyses of AP showed low toxicity and good tolerance in many diseases, and that many neuropsychiatric diseases are based on GABA receptor function disorder, AP has low molecular weight, and it can pass through blood–brain barrier easily and has undertaken many essential tasks such as learning, memory, and mood. If GABA-A receptors are thought to be a major task in migraine pathophysiology, we believe that similar positive effects on the diagnosis and progression of the disease will be provided by AP.[19]

In a recent study, Koverech et al. found that AP levels were increased in episodic migraine and chronic migraine patients than in controls, whereas they were reduced in patients affected by cluster headache.[20] These findings do not coincide with our results. First of all, this difference may be due to the difference in the patient population in the studies. In our study, we compared patients with migraine with control.

There were some limitations to this study. First, our study was conducted in a single center and with few patients. Second, comorbid diseases and treatment models which might be related to migraine were not included in the study, which stands out as the most important limitation.


  Conclusion Top


This study showed that low AP levels were detected in migraine patients. These markers may contribute to our understanding of the pathophysiology of migraine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Marx J, Walls R, Hockberger R. Rosen's Emergency Medicine-Concepts and Clinical Practice E-Book. 8th ed. Cambridge, Massachusetts: Elsevier Health Sciences; 2013. p. 176-183.  Back to cited text no. 1
    
2.
Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd ed. Cephalalgia 2004;24 Suppl 1:9-160  Back to cited text no. 2
    
3.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163-96.  Back to cited text no. 3
    
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Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the United States: Updated statistics from government health surveillance studies. Headache 2015;55:21-34.  Back to cited text no. 4
    
5.
Ropper A, Samuels MA. Adams and victiors principles of Neurology. 9th ed. Philadelphia: McGraw Hill; 2009. p. 271-301.  Back to cited text no. 5
    
6.
Von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The strengthening of the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting of observational studies. PLos Med 2007;4:1623-7.  Back to cited text no. 6
    
7.
Schramm S, Uluduz D, Gouveia RG, Jensen R, Siva A, Uygunoglu U, et al. Headache service quality: Evaluation of quality indicators in 14 specialist-care centres. J Headache Pain 2016;17:111.  Back to cited text no. 7
    
8.
Ertas M, Baykan B, Orhan EK, Zarifoglu M, Karli N, Saip S, et al. One-year prevalence and the impact of migraine and tension-type headache in Turkey: A nationwide home-based study in adults. J Headache Pain 2012;13:147-57.  Back to cited text no. 8
    
9.
MacGregor EA. Migraine management during menstruation and menopause. Continuum (Minneap Minn) 2015;21:990-1003.  Back to cited text no. 9
    
10.
Hossain MA, Mohammad, QD, Habib M, Hoque MA, Alam MB, Hussain ME. Severity of migraine with or without comorbidities: A comparative study. J National Inst Neurosci Bangladesh 2015;2:33-36.  Back to cited text no. 10
    
11.
Chiapponi C, Piras F, Piras F, Caltagirone C, Spalletta G. GABA system in schizophrenia and mood disorders: A mini review on third-generation imaging studies. Front Psychiatr 2016;7:61.  Back to cited text no. 11
    
12.
Ishikawa M, Yoshitomi T, Covey DF, Zorumski CF, Izumi Y. Neurosteroids and oxysterols as potential therapeutic agents for glaucoma and Alzheimer's disease. Neuropsychiatry (London) 2018;8:344-59.  Back to cited text no. 12
    
13.
Naylor JC, Kilts JD, Szabo ST, Dunn CE, Keefe FJ, Tupler LA, et al. Allopregnanolone levels are inversely associated with self-reported pain symptoms in US Iraq and Afghanistan-era veterans: Implications for biomarkers and therapeutics. Pain Med 2016;17:25-32.  Back to cited text no. 13
    
14.
Perkins EC, Jeffrey N. Neurosteroids in the pathophysiology and treatment of mood and anxiety disorders. Curr Treat Options Psychiatry 2018;5:377-400.  Back to cited text no. 14
    
15.
Joshi S, Kapur J. Neurosteroid regulation of GABAA receptors: A role in catamenial epilepsy. Brain Res 2019;1703:31-40.  Back to cited text no. 15
    
16.
Frye CA, Paris JJ, Walf AA, Rusconi JC. Effects and mechanisms of 3α,5α,-THP on emotion, motivation, and reward functions involving pregnane xenobiotic receptor. Front Neurosci 2011;5:136.  Back to cited text no. 16
    
17.
Sergeeva EG, Espinosa-Garcia C, Atif F, Pardue MT, Stein DG. Neurosteroid allopregnanolone reduces ipsilateral visual cortex potentiation following unilateral optic nerve injury. Exp Neurol 2018;306:138-48.  Back to cited text no. 17
    
18.
Littlejohn E, Boychuk C. Acute neurosteroid treatment with allopregnanolone enhances dorsal vagal motor neuron inhibition. FASEB J 2019;33:556-8.  Back to cited text no. 18
    
19.
Tardiolo G, Bramanti P, Mazzon E. Overview on the effects of N-acetylcysteine in neurodegenerative diseases. Molecules 2018;23:3305. doi: 10.3390/molecules23123305.  Back to cited text no. 19
    
20.
Koverech A, Cicione C, Lionetto L, Maestri M, Passariello F, Sabbatini E, et al. Migraine and cluster headache show impaired neurosteroids patterns. J Headache Pain 2019;20:61.  Back to cited text no. 20
    


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