Male-female comparison of vasomotor effects of circulating hormones in human intracranial arteries

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Abstract

Background

The purpose of this study was to examine whether there are sex differences in vasomotor responses and receptor localization of hormones and neuropeptides with relevance to migraine (vasopressin, oxytocin, estrogen, progesterone, testosterone, amylin, adrenomedullin and calcitonin gene-related peptide (CGRP)) in human intracranial arteries.

Methods

Human cortical cerebral and middle meningeal arteries were used in this study. The tissues were removed in conjunction with neurosurgery and donated with consent. Vasomotor responses of arteries, after exposure to hormones or neuropeptides, were recorded using a wire myograph. Immunohistochemistry was performed to examine the expression and localization of their receptors within human intracranial arteries.

Results

Vasopressin showed the strongest contractile responses, followed by oxytocin and progesterone. CGRP displayed the strongest vasodilatory response when compared to adrenomedullin, amylin, testosterone and estrogen. No significant differences were observed in vasomotor responses between male and female arteries. The vasomotor effects were supported by the presence of corresponding receptors in the vascular smooth muscle cells. Estrogen receptors (ERα and ERβ), progesterone receptor (PR), vasopressin 1a receptor (V1aR), and the oxytocin receptor (OTR) were expressed in the walls of both cerebral arteries overlying the cerebral cortex and intracranial arteries of the dura mater. ERα, V1aR, and PR were found to be localized in both smooth muscle cells and endothelium, whereas OTR was exclusively located within the smooth muscle cells.

Conclusions

Hypothalamic, sex hormones and the pancreas hormone (amylin) receptors are expressed in the human intracranial artery walls. The vasomotor responses revealed no sex differences, however contractile responses to vasopressin was higher and more potent in MMA compared to CCA when pooling data from both sexes. Overall, the hormones estrogen, progesterone and oxytocin, which drop in circulating levels at onset of menstruation, only showed modest vasomotor responses as compared to CGRP. This suggests that their role in inducing menstrual migraine attacks is not directly related to vasomotor responses.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s10194-024-01933-w.

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Most cited references 34

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Sex differences in the epidemiology, clinical features, and pathophysiology of migraine.

Kjersti Vetvik, E Anne MacGregor (2017)

Migraine is two to three times more prevalent in women than men, and women report a longer attack duration, increased risk of headache recurrence, greater disability, and a longer period of time required to recover. Conditions recognised to be comorbid with migraine include asthma, anxiety, depression, and other chronic pain conditions, and these comorbidities add to the amount of disability in both sexes. Migraine-specifically migraine with aura-has been identified as a risk factor for vascular disorders, particularly in women, but because of the scarcity of data, the comparative risk in men has yet to be established. There is evidence implicating the role of female sex hormones as a major factor in determining migraine risk and characteristics, which accounts for sex differences, but there is also evidence to support underlying genetic variance. Although migraine is often recognised in women, it is underdiagnosed in men, resulting in suboptimal management and less participation of men in clinical trials.

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Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study.

Dawn Buse, Elizabeth W Loder, Jennifer A Gorman … (2013)

The strikingly higher prevalence of migraine in females compared with males is one of the hallmarks of migraine. A large global body of evidence exists on the sex differences in the prevalence of migraine with female to male ratios ranging from 2:1 to 3:1 and peaking in midlife. Some data are available on sex differences in associated symptoms, headache-related disability and impairment, and healthcare resource utilization in migraine. Few data are available on corresponding sex differences in probable migraine (PM) and other severe headache (ie, nonmigraine-spectrum severe headache). Gaining a clear understanding of sex differences in a range of severe headache disorders may help differentiate the range of headache types. Herein, we compare sexes on prevalence and a range of clinical variables for migraine, PM, and other severe headache in a large sample from the US population. This study analyzed data from the 2004 American Migraine Prevalence and Prevention Study. Total and demographic-stratified sex-specific, prevalence estimates of headache subtypes (migraine, PM, and other severe headache) are reported. Log-binomial models are used to calculate sex-specific adjusted prevalence ratios and 95% confidence intervals for each across demographic strata. A smoothed sex prevalence ratio (female to male) figure is presented for migraine and PM. One hundred sixty-two thousand seven hundred fifty-six individuals aged 12 and older responded to the 2004 American Migraine Prevalence and Prevention Study survey (64.9% response rate). Twenty-eight thousand two hundred sixty-one (17.4%) reported "severe headache" in the preceding year (23.5% of females and 10.6% of males), 11.8% met International Classification of Headache Disorders-2 criteria for migraine (17.3% of females and 5.7% of males), 4.6% met criteria for PM (5.3% of females and 3.9% of males), and 1.0% were categorized with other severe headache (0.9% of females and 1.0% of males). Sex differences were observed in the prevalence of migraine and PM, but not for other severe headache. Adjusted female to male prevalence ratios ranged from 1.48 to 3.25 across the lifetime for migraine and from 1.22 to 1.53 for PM. Sex differences were also observed in associated symptomology, aura, headache-related disability, healthcare resource utilization, and diagnosis for migraine and PM. Despite higher rates of migraine diagnosis by a healthcare professional, females with migraine were less likely than males to be using preventive pharmacologic treatment for headache. In this large, US population sample, both migraine and PM were more common among females, but a sex difference was not observed in the prevalence of other severe headache. The sex difference in migraine and PM held true across age and for most other sociodemographic variables with the exception of race for PM. Females with migraine and PM had higher rates of most migraine symptoms, aura, greater associated impairment, and higher healthcare resource utilization than males. Corresponding sex differences were not observed among individuals with other severe headache on the majority of these comparisons. Results suggest that PM is part of the migraine spectrum whereas other severe headache types are not. Results also substantiate existing literature on sex differences in primary headaches and extend results to additional headache types and related factors. © 2013 American Headache Society.

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Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25.

Debbie Hay, Michael Garelja, David R. Poyner … (2018)

The calcitonin/CGRP family of peptides includes calcitonin, α and β CGRP, amylin, adrenomedullin (AM) and adrenomedullin 2/intermedin (AM2/IMD). Their receptors consist of one of two GPCRs, the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CLR). Further diversity arises from heterodimerization of these GPCRs with one of three receptor activity-modifying proteins (RAMPs). This gives the CGRP receptor (CLR/RAMP1), the AM1and AM2receptors (CLR/RAMP2 or RAMP3) and the AMY1,AMY2and AMY3receptors (CTR/RAMPs1-3 complexes, respectively). Apart from the CGRP receptor, there are only peptide antagonists widely available for these receptors, and these have limited selectivity, thus defining the function of each receptor in vivo remains challenging. Further challenges arise from the probable co-expression of CTR with the CTR/RAMP complexes and species-dependent splice variants of the CTR (CT(a)and CT(b)). Furthermore, the AMY1(a)receptor is activated equally well by both amylin and CGRP, and the preferred receptor for AM2/IMD has been unclear. However, there are clear therapeutic rationales for developing agents against the various receptors for these peptides. For example, many agents targeting the CGRP system are in clinical trials, and pramlintide, an amylin analogue, is an approved therapy for insulin-requiring diabetes. This review provides an update on the pharmacology of the calcitonin family of peptides by members of the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology and colleagues.

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Author and article information

Contributors

Jacob C. A. Edvinsson: jacob.edvinsson@med.lu.se

Journal

Journal ID (nlm-ta): J Headache Pain

Journal ID (iso-abbrev): J Headache Pain

Title: The Journal of Headache and Pain

Publisher: Springer Milan (Milan )

ISSN (Print): 1129-2369

ISSN (Electronic): 1129-2377

Publication date (Electronic): 11 December 2024

Publication date PMC-release: 11 December 2024

Publication date Collection: 2024

Volume: 25

Issue: 1

Electronic Location Identifier: 216

Affiliations

[1 ]Department of Clinical Sciences, Faculty of Medicine, Lund University, ( https://ror.org/012a77v79) Getingevagen 4, Lund, 22185 Sweden

[2 ]GRID grid.411843.b, ISNI 0000 0004 0623 9987, Department of Neurosurgery, , University Hospital, ; Lund, Sweden

Article

Publisher ID: 1933

DOI: 10.1186/s10194-024-01933-w

PMC ID: 11633024

PubMed ID: 39663536

SO-VID: b3b30de4-4cfa-4fe7-b872-2e9d43f2ef18

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 6 November 2024

Date accepted : 3 December 2024

Funding

Funded by: Lund University

Open Access :

Open access funding provided by Lund University.

Custom metadata

ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: estrogen,oxytocin,vasopressin,progesterone,testosterone,adrenomedullin,amylin,cgrp

Data availability:

ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: estrogen, oxytocin, vasopressin, progesterone, testosterone, adrenomedullin, amylin, cgrp

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Male-female comparison of vasomotor effects of circulating hormones in human intracranial arteries

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Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Supplementary Information

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Cardiovascular Innovations and Applications

Most cited references 34

Sex differences in the epidemiology, clinical features, and pathophysiology of migraine.

Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study.

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25.

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