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Abstract

Background

Migraine prevalence and levels of calcitonin gene-related peptide (CGRP), a peptide involved in migraine pathophysiology, differ between men and women, and appear to be affected by changes in sex hormones. The present study investigated the sex-specific responses to CGRP in human isolated arteries.

Methods

CGRP-induced relaxation of 62 (28 men and 34 women) human isolated middle meningeal arteries (HMMA) and 139 (69 men and 70 women) human isolated coronary arteries (HCA) was compared between men and women in groups <50 years and ≥50 years of age as a proxy for pre- and postmenopausal status in women, as well as matched-age groups for men.

Results

In HCA, no differences were observed between male and female tissue, or between the different age groups. However, in HMMA, the maximum response was significantly smaller and CGRP was less potent in females <50 compared with males <50 years of age. No differences were observed between the older age groups.

Conclusions

Sex differences were observed for CGRP-induced relaxation of HMMA, but not HCA. These differences could arise from differential receptor expression in the vascular beds combined with the effect of sex hormones on CGRP and subsequent receptor desensitization.

Keywords

CGRP estrogen human arteries sex differences testosterone vasodilation

Introduction

Migraine prevalence differs between men and women and varies throughout life, with a similar prevalence before puberty and after menopause, and a three-fold higher prevalence in women during their reproductive years (1). In addition, women often experience more severe headache attacks and a higher headache-related disability (1,2). These differences are presumed to result from hormonal influences because varying migraine incidence can be observed during the menstrual cycle, pregnancy and perimenopause, with a lower susceptibility during rising estrogen levels and an increased susceptibility coinciding with a drop in estrogen levels or hormonal fluctuations (3 –5). Moreover, oral contraceptives and hormonal replacement therapy can affect migraine headache frequency (6), with male-to-female transgenders undergoing hormonal therapy experiencing similar rates compared with the general female population (7). In addition, it was demonstrated that male patients with migraine had increased estradiol levels when compared with male controls, again highlighting the relation between sex hormones and migraine (8).

The pathophysiology of migraine headache includes activation of the trigeminovascular system and the release of the neuropeptide and potent vasodilator calcitonin gene-related peptide (CGRP). Both the CGRP peptide and the CGRP receptor are targets of novel anti-migraine medication (9), such as the small-molecule CGRP-receptor antagonists called gepants (e.g. atogepant, olcegepant, rimegepant, ubrogepant and zavegepant). Interestingly, increased plasma CGRP levels were measured in women compared with men, with even higher levels reported in women using combined contraceptive pills (10), and increased CGRP plasma and tear fluid levels could be detected in migraine patients compared with healthy controls during the menstruation in participants not using hormonal contraceptives, whereas no differences between migraine patients and controls could be observed for participants using combined oral contraception or in the postmenopause (11). These studies suggest that female sex hormones affect CGRP levels, although a clear distinction between measurements of the two isoforms of CGRP (i.e. alpha and beta CGRP) is not always reported.

Receptors of estrogen, progesterone and testosterone are widely expressed in the cranial vasculature and trigeminovascular system (12). A preclinical study in anesthetized rats showed that sensitization of the trigeminal system changes throughout the rat estrous cycle, with enhanced sensitization during the decline of ovarian steroid hormones (13). Moreover, 17β-estradiol supplementation enhanced vasodilatory responses to periarterial electrical stimulation of the middle meningeal artery in ovariectomized rats, which is likely mediated by increased release of CGRP (14). In addition, treatment of rats with 17β-estradiol potentiated the relaxation to CGRP in isolated arteries (15).

Considering the interactions among migraine, sex and CGRP, as well as the possible involvement of the vasculature during a migraine attack and as a target for migraine medication, we investigated the sex-specific responses to CGRP in human isolated arteries. Human middle meningeal arteries (HMMA) are innervated by the trigeminal nerve and CGRP signalling in the trigeminovascular system could be relevant for migraine pathophysiology. In addition, CGRP-induced relaxation of human coronary arteries (HCA) is relevant in the context of possible cardiovascular side effects of the novel anti-CGRP(-receptor) blockers. Therefore, CGRP-induced relaxation of HMMA and HCA was compared between men and women in different age groups. Based on the effect of sex hormones on CGRP, differences between pre- and postmenopausal women and men were hypothesized in both vascular beds. Moreover, an explorative analysis was performed to determine whether sex differences exist in the potency of olcegepant to inhibit CGRP-induced relaxation of these human arteries.

Methods

HCA were isolated from hearts of 139 heart valve donors (69 males and 70 females, age range 3–70 years) between 2001 and 2023. Hearts from Dutch post-mortem donors were provided by ETB-BISLIFE (Heart Valve Department, Beverwijk, The Netherlands, located in Rotterdam until 2016) following removal of the aortic and pulmonary valve for homograft valve transplantation. Donor screening and acceptance was performed by the Dutch Transplant Foundation (Leiden, The Netherlands). All donors gave permission for research. Immediately after circulatory arrest, the hearts were harvested and stored at 4°C in a sterile organ protecting solution and brought to the laboratory within the first 24 h after death. Distal portions of coronary arteries were isolated and subsequently stored in oxygenated and carbonated Krebs solution (118 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl₂, 1.2 mM MgSO₄, 1.2 mM KH₂PO₄, 25 mM NaHCO₃ and 8.3 mM glucose, pH 7.4) at 4°C until the start of the experiment.

HMMA were obtained from 62 patients (28 males, 34 females, age range 3–78 years) undergoing neurosurgical procedures between 2002 and 2023 at the Erasmus Medical Center (Rotterdam, The Netherlands). Middle meningeal arteries were stored in Medium 199 and transported to the laboratory immediately. Subsequently, surrounding tissue was removed and the artery was stored in a cold oxygenated Krebs solution (16) (119 mM NaCl, 4.7 mM KCl, 1.25 mM CaCl₂, 1.2 mM MgSO₄, 1.2 mM KH₂PO₄, 25 mM NaHCO₃ and 11.1 mM glucose, pH 7.4) at 4°C until the start of the experiment.

For functional experiments, human arteries were cut into 2-mm segments and mounted in Mulvany myograph organ baths (Danish Myo Technology, Aarhus, Denmark), using stainless-steel wires (diameter 40 µm). Organ baths were filled with oxygenated and carbonated Krebs solution at 37°C. Vessel segments were left to equilibrate. Next, the segments were stretched to a tension normalized to 0.9 times the estimated diameter at a transmural pressure of 100 mmHg (17). Data were recorded using LabChart data acquisition software (AD instruments Ltd, Oxford, UK). First, all segments were exposed to 30 mM KCl, followed by 100 mM KCl, aiming to determine whether the segments are still viable and to serve as a reference contraction to allow comparison between conditions or tissues. After washing twice, the vessels were pre-contracted using 30 mM KCl, and exposed to increasing concentrations (from 0.01 nM to 1 µM, in half logarithmic steps) of human α-CGRP (Polypeptide Group, Baar, Switzerland). The subsequent concentration of CGRP was added after a plateau for the response to the previous concentration was reached, or after at least six minutes in case of no clear response to CGRP. Some segments were incubated with 1 µM olcegepant (MedChemExpress, Monmouth Junction, NJ, USA) 30 min before the first concentration of CGRP to investigate the inhibition of CGRP-induced relaxation.

Concentration–response curves with a sigmoidal shape were obtained and analysed using Prism 8 (GraphPad Software Inc., San Diego, CA, USA). Non-linear regression analysis was used to determine the drug potency (pEC₅₀). Considering the interaction between sex steroids and CGRP, differences between pre- and postmenopausal women were hypothesized. In the present study, the menopausal status of the individual women was unknown, and therefore they were classified into two age categories approximately representing pre- and postmenopausal women, with one group with ages below 50 years and one group aged 50 years and older. The age limit was set at <50 years according to the average age of Dutch women reaching menopause (18). With the purpose of age matching, men were subsequently split into the same age categories, resulting in four different groups for both HCA and HMMA (i.e. women <50, women ≥50 years, men <50 and men ≥50 years). Information on the use of oral contraceptives or hormonal replacement therapy was not available for HCA or HMMA donors. The maximum relaxation response (E_max) to CGRP and the pEC₅₀ values was compared between the groups using one-way analysis when comparing multiple groups, and, when significant, a Bonferroni's multiple comparisons test was performed. A t-test was used for a comparison of two groups. In addition, the maximum response to CGRP and the potency of CGRP was plotted against the age of the donor for both HMMA and HCA. Linear regression was used to determine the slope. p < 0.05 was considered statistically significant.

The potency of olcegepant in HMMA and HCA was calculated for each tissue incubated with olcegepant, resulting in pK_b or pA₂ values. The potency was plotted separately for men and women against their age, and a linear regression analysis was performed to determine whether the potency of olcegepant changes with age.

Results

In HCA, the concentration–response curves to CGRP did not differ between any of the four groups based on E_max (female (F) < 50 77.9 ± 5.1, F ≥ 50 83.4 ± 3.1, male (M) < 50 82.7 ± 3.1 and M ≥ 50 89.3 ± 2.7) or pEC₅₀ (F < 50 8.31 ± 0.17, F ≥ 50 8.39 ± 0.09, M < 50 8.08 ± 0.17 and M ≥ 50 8.40 ± 0.11) (Figure 1). Moreover, no sex differences were observed when all women and all men were compared, and no age differences could be detected in HCA.

Figure 1.

Concentration–response curve to human α-CGRP in human isolated coronary arteries. Concentration–response curves are presented as mean ± SEM. Tissues were obtained from female donors below 50 years of age (female (F) < 50; n = 22, age 41 ± 10 years), female donors of 50 years and older (F ≥ 50; n = 48, age 59 ± 6 years), male donors below 50 years of age (male (M) < 50; n = 27, age 33 ± 14 years) and male donors of 50 years and older (M ≥ 50; n = 42, age 57 ± 4 years). Age, E_max and pEC₅₀ are presented as the mean ± SD.

In HMMA, CGRP-induced vasodilation significantly differed among the four groups (E_max p = 0.0027, pEC₅₀ p = 0.048) (Figure 2). Relaxations to CGRP were not different between men and women of 50 years and older, either in maximum response to CGRP or potency (E_max 74.5 ± 5.9 and 78.0 ± 4.3 and pEC₅₀ 8.15 ± 0.12 and 8.12 ± 0.15, respectively). However, the response to CGRP was significantly smaller and CGRP was less potent in females younger than 50 years (E_max 60.2 ± 6.3 and pEC₅₀ 7.95 ± 0.16) compared with males younger than 50 years (E_max 90.4 ± 3.0 and pEC₅₀ 8.53 ± 0.10, E_max p = 0.0013 and pEC₅₀ p = 0.046). As a result of these large differences in young females and males, the E_max of the total group of women was lower than the E_max of males (E_max 71.7 ± 3.8 vs 82.5 ± 3.6, respectively, p = 0.047), even though no differences existed between males and females over the age of 50 years.

Figure 2.

Concentration–response curve to human α-CGRP in human middle meningeal arteries. Concentration–response curves are presented as mean ± SEM. Tissues were obtained from female donors below 50 years of age (female (F) < 50, n = 12, age 41 ± 7 years), female donors of 50 years and older (F ≥ 50, n = 22, age 61 ± 9 years), male donors below 50 years of age (male (M) < 50, n = 14, age 36 ± 13 years) and male donors of 50 years and older (M ≥ 50, n = 14, age 59 ± 6 years). All data are represented as the mean ± SEM, **p < 0.01, ***p < 0.001. E_max and pEC₅₀ are presented as the mean ± SD.

To further elucidate the effect of age and sex on CGRP responses, the maximum response to CGRP and the pEC₅₀ was plotted against the age of the donor for men and women separately, in both HMMA (Figure 3a, b) and HCA (Figure 3c, d). In HMMA, the maximum response to CGRP was significantly negatively correlated with age for men (slope = –0.538, 95% confidence interval (CI) = −0.992 to −0.084, p = 0.0220). For women, a positive trend was observed but the correlation was not significant (slope = 0.427, 95% CI = −0.170 to 1.023). However, the slope for men and women was significantly different (p = 0.0113). For the potency of CGRP in HMMA (Figure 3b) or the functional responses in HCA (Figure 3c, d), no significant correlation could be observed with age.

Figure 3.

Relationship between age and CGRP response for both men and women in different vascular tissues. (a) Maximum response to CGRP in human middle meningeal artery (female, n = 34; male, n = 28). (b) Potency of CGRP in human middle meningeal artery (female, n = 34; male, n = 28). (c) Maximum response to CGRP in human coronary artery (female, n = 70; male, n = 69). (d) Potency of CGRP in human coronary artery (female, n = 70; male, n = 69). The 95% CI of the slope is displayed and specified below the graphs.

CGRP was equipotent in HCA (pEC₅₀ 8.32 ± 0.06) and HMMA (pEC₅₀ 8.19 ± 0.07) when sex and age were not taken into account. Because differences in response to CGRP were observed in HMMA based on age and sex, and considering the observed sex differences in response to other types of anti-migraine medication (e.g. triptans, propranolol) (19,20), an explorative analysis was performed to investigate whether sex differences in potency of the CGRP receptor antagonist olcegepant exist in the two vascular tissues as well. The potency of olcegepant was plotted against the age of the donor for both men and women. No clear relation between age and potency of olcegepant could be observed for either men or women in HCA or HMMA (Figure 4). Moreover, the potency of olcegepant did not differ between men and women in HCA (p = 0.3740) or human middle meningeal arteries (p = 0.7281), nor did the potency of olcegepant between the two vascular tissues when comparing the pK_b for olcegepant at a concentration of 1 µM in HCA with the pA₂ of olcegepant in HMMA (HCA 9.07 ± 0.23 and HMMA 9.42 ± 0.28, p = 0.347).

Figure 4.

Relationship between age and potency of olcegepant for both men and women in different vascular tissues. (a) Potency of olcegepant in the human coronary artery (female, n = 8; male, n = 9). (b) Potency of olcegepant in the human middle meningeal artery (female, n = 12; male, n = 6).

Discussion

In HCA, no differences in the functional response to CGRP were observed between male and female tissue or between the different age groups. By contrast, in HMMA, the maximum response was smaller and CGRP was less potent in females below the age of 50 years compared with males below the age of 50 years. For the older age groups, no differences were observed. Moreover, the maximum response to CGRP in HMMA showed a significant negative correlation with age for males, and differed significantly between males and females, whereas no correlation between age and functional responses could be observed in HCA. Therefore, the results of the present study suggest that the response to exogenous CGRP is not dependent on age and sex in human isolated coronary arteries, whereas it is in human middle meningeal arteries.

CGRP-induced relaxation occurs after binding of CGRP to its receptor. Therefore, the effects induced by exogenous CGRP on the human middle meningeal arteries could possibly be explained by different receptor activation in the different age and sex groups. Prolonged exposure to an agonist can result in desensitization or downregulation of G-protein coupled receptors (21), which could occur for the G-protein coupled CGRP receptors after prolonged exposure to CGRP as well; for example, in the case of increased CGRP levels. However, considering that differences were observed for HMMA but not for HCA, fluctuating systemic CGRP levels throughout life alone are not sufficient to explain the findings in the present study. Because the trigeminovascular system, and therein the middle meningeal artery, is densely innervated, including fibers that contain CGRP (22), local CGRP levels could differ between the coronary circulation and the meningeal circulation. Possibly, enhanced local CGRP release by the trigeminal nerve results in a different exposure to CGRP in the different vascular beds. In addition, CGRP release from the rat dura mater was shown to be higher in female rats compared with male rats (23). Alternatively, receptors in the meningeal vasculature could be more susceptible to desensitization, and thereby be more affected by CGRP exposure during life. Another plausible explanation for the differences between human middle meningeal arteries and human coronary arteries is differential expression of receptors within the CGRP receptor family. The canonical CGRP receptor consists of calcitonin-like receptor (CLR) coupled to receptor activity-modifying protein 1 (RAMP1), and is similar to other receptors within the same family, such as the adrenomedullin receptor, consisting of CLR coupled to RAMP2 (24). Recently, our laboratory demonstrated that mainly the canonical CGRP receptor is present in HCA, whereas, in HMMA, both the canonical CGRP receptor and the adrenomedullin receptor are expressed (25). Moreover, desensitization differs for the CGRP receptor and the adrenomedullin receptor (26). CGRP can bind and activate both these receptors, although it is more potent at the canonical CGRP receptor. However, exposure of the adrenomedullin receptor to CGRP can result in desensitization of this receptor and a diminished response to subsequent exposure. Therefore, fluctuating CGRP levels could possibly affect receptors in the meningeal vasculature, while leaving the coronary circulation unaffected. In addition, it should be noted that the human coronary arteries were isolated from hearts of deceased organ donors, which theoretically could have affected the response to CGRP. However, because average responses did not differ between HCA and HMMA, receptor function is assumed to remain stable in these tissues.

Following the hypothesis that HMMA are more sensitive to fluctuating CGRP levels, whether this is a result of enhanced local release of CGRP, increased susceptibility to receptor desensitization or downregulation, or differential receptor expression in the vascular beds, the differences observed for sex and age in the middle meningeal arteries could possibly be explained by changing CGRP levels throughout life. Previously, systemic plasma levels of CGRP were shown to be higher in women compared with men, and to be affected by sex hormones, as demonstrated by increased CGRP levels in women using hormonal contraception (10). This could suggest a positive effect of estrogen on CGRP levels. This effect is also observed in ovariectomized rats, which show an increase in CGRP after treatment with estrogen (27). Moreover, 17β-estradiol treatment decreased expression of CLR, RAMP1, RAMP2 and RAMP3 in the uterus of ovariectomized (28) and the placenta of pregnant rats (29), which could result from increased exposure to CGRP and subsequent receptor desensitization or downregulation. By contrast, other studies have shown increased expression of CGRP in the trigeminal ganglion and several structures within the central nervous system after ovariectomy in rats, which decreased after treatment with estrogen (12), and increased CGRP-induced vasodilation responses in arteries from ovariectomized rats treated with 17β-estradiol (15). Interestingly, as observed for menstrual migraine and migraine headache attack frequency during pregnancy, it is not the high levels of estrogen that appear to be associated with a migraine attack, but rather the sudden drop in estrogen levels (1). In accordance, capsaicin-induced increases in dermal blood flow, which are likely mediated by CGRP, appear to be larger during menstruation in healthy females, coinciding with the drop in estrogen levels (30). Regardless of whether the high levels of estrogen or the fluctuations in estrogen determine the effect on CGRP levels, these are proposed to fluctuate throughout life based on the presence of sex hormones, which could subsequently affect CGRP receptor functioning through desensitization or downregulation. Moreover, the decreased estrogen fluctuations after menopause could result in a decreased exposure to CGRP and possibly less receptor desensitization in postmenopausal women.

In HMMA of men, a significant negative correlation was observed between the maximum response to CGRP and age. Considering that estrogen levels remain relatively constant in males, estrogen levels alone are not sufficient to explain the responses to CGRP in male meningeal arteries. Interestingly, previous studies revealed that male migraine patients exhibit a lower ratio of free testosterone to 17β-estradiol (8) and more often suffer from symptoms associated with androgen deficiency compared with healthy controls (31). Possibly, the ratio between these two sex hormones could help explain the findings of the present study as well. Testosterone levels increase in males during puberty and slowly decrease with increasing age (32), and a small study showed that treatment with testosterone reduced the severity of migraine attacks in female migraine patients with symptoms of androgen deficiency (33). Interestingly, in a preclinical study using rat basilar arteries, relaxation to CGRP was decreased in aging rats compared with younger controls, which was reversed by treatment with testosterone. By contrast, the protein expression of the CLR and RAMP1 subunits of the CGRP receptor was increased in these older rats, whereas testosterone itself was shown to increase the expression of these subunits as well (34). Although these results do not show a clear correlation between receptor expression and functional results, it does suggest that testosterone increases expression of the CGRP receptor. If this would also occur in the human middle meningeal arteries, it could explain why the maximum response to exogenous CGRP is increased in young males, with high testosterone levels, and decreases once males get older and testosterone levels slowly fall.

Together, the effect of both estrogen and testosterone on CGRP levels, and the subsequent effect of receptor downregulation or desensitization as a result of prolonged exposure, could possibly explain the observed differences in the current study in human middle meningeal arteries (Figure 5). In young women, estrogen levels are high and testosterone levels are low, resulting in a high estradiol/testosterone ratio, which possibly results in high CGRP levels and increased desensitization and downregulation of receptors, with a decreased CGRP response in our experimental set-up as a consequence. In postmenopausal women, estrogen levels and fluctuations decrease, thereby lowering CGRP levels and consequent CGRP receptor downregulation, resulting in an increased response to exogenous CGRP in our experimental model. Young males have low estrogen levels and high testosterone levels, which could result in low CGRP levels or high CGRP receptor expression, and thus an increased response in our ex vivo experimental set-up. Once males get older, their testosterone levels start to decline, possibly resulting in lower CGRP receptor expression and consequent lower response to CGRP in HMMA. The exact mechanism of how sex hormones affect CGRP levels and CGRP receptors should be investigated in future research. When considering the ratio between estradiol and testosterone, it is important to note that testosterone is a precursor of estradiol, which could imply that changes in testosterone also affect estradiol levels. However, aromatase activity, which is responsible for the conversion of testosterone to estradiol, increases with aging in men, resulting in an altered ratio of estradiol and testosterone (35). In addition, it should be noted that the CGRP response in very young donors could potentially affect the data, considering their prepubertal hormonal status. However, in the present study, the few young donors did not affect the overall conclusion.

Figure 5.

Hypothesis for the relation between sex hormones, CGRP levels and functional responses in the human middle meningeal artery. The expected ratio between estradiol and testosterone varies throughout life and differs between men and women (bar graphs). Both estradiol and testosterone levels could affect CGRP levels, of which increased exposure possibly results in CGRP receptor desensitization or downregulation in the human middle meningeal artery. The current theory is based on the idea that the meningeal vasculature is more sensitive to fluctuating CGRP levels compared with the coronary vasculature, possibly resulting from enhanced local release of CGRP as a result of trigeminal innervation, or differential receptor expression in the vascular beds resulting in altered susceptibility to receptor desensitization or downregulation.

Since the meningeal vasculature is innervated by the trigeminal nerve, this is a highly relevant structure in the pathophysiology of migraine. Interestingly, migraine is much more prevalent in young women compared with men or women after menopause. Therefore, it is not surprising that this group shows different responses to CGRP in the meningeal arteries. Unfortunately, the functional data cannot be linked to migraine status because this information is unknown from our tissue donors. Future experiments should determine whether the functional response to CGRP is altered in migraine patients. In addition, it is not known whether the patients had any (history of) disease or used any type of medication, which could have influenced the results in the present study.

The preliminary analysis with olcegepant showed that the response to CGRP receptor blockade does not differ for men and women or with increasing age. The dataset is relatively small, but no trend whatsoever can be observed. Interestingly, for another class of specific anti-migraine medication, comprising the 5-HT_1B/1D receptor agonists named triptans, sex differences have been reported, with women experiencing more adverse events and higher recurrence rates compared with men (19). Moreover, propranolol, which is used for migraine prophylaxis, was shown to inhibit capsaicin-induced increases in dermal blood flow in males, but not in females (20). Clinical data regarding gepants are often not powered to detect sex differences, and the majority of participants are female. However, a recent subgroup analysis of clinical data of ubrogepant, rimegepant and zavegepant showed an enhanced efficacy in women compared with men concerning pain freedom and freedom from most bothersome symptom 2 h after intake (36). Because, in the present study, no differences for age or sex were observed for olcegepant potency in human arteries, such differences in clinical efficacy of gepants may probably not be related to pharmacodynamic differences in potency of the gepants between patient groups, or at least not in the vascular tissues studied here. Based on the similar target for gepants and the monoclonal antibody erenumab, no differences in potency of erenumab are expected for men and women. However, previous research showed that gepants can elicit additional effects on top of a maximum effect of erenumab in human isolated arteries, suggesting a possible different mechanism of action (37). Therefore, additional studies on potential sex differences for erenumab are needed. In addition, the current methodology is not suitable for investigating whether pharmacokinetic differences could cause differences between men and women in treatment response.

Conclusions

In the present study with a unique number of human vascular tissue samples, differences were observed for CGRP-induced relaxation of human middle meningeal arteries, but not human coronary arteries. These differences could arise from differential receptor expression in the different vascular beds together with changing sex hormone levels with aging and their effect on CGRP. Increased CGRP levels could potentially induce receptor desensitization, resulting in a smaller response to CGRP in young females and a larger response to CGRP in young males. Clinical implications

CGRP-induced relaxation is smaller in young women (<50 years) compared with young men in human middle meningeal arteries.

Sex differences are not observed for human coronary arteries.

The potency of olcegepant does not differ between men and women and does not change with increasing age.

Footnotes

Declaration of conflicting interests

AMvdB received personal fees (fees as advisor or speaker, consultancy, any other) from Allergan-Abbvie, Lilly, Novartis and Teva. AMvdB also received research support from Novartis, Satsuma and Tonix, as well as independent research support from the Dutch Research Council and the Netherlands Organisation for Health Research and Development.

Funding

This research was supported by Vici grant 09150181910040 from the Dutch Research Council.

ORCID iD

Tessa de Vries

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Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Results

Discussion

Conclusions

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

References