Considerations for hormonal therapy in migraine patients:a critical review of current practice

Introduction: Migraine, a neurovascular headache disorder, is a leading cause of disability worldwide. Within the multifaceted pathophysiology of migraine, hormonal fluctuations play an evident triggering and exacerbating role, pointing toward the need for identification and proper usage of both existing and new hormonal targets in migraine treatment. Areas covered: With a threefold higher incidence of migraine in women than in men, the authors delve into sex hormone-related events in migraine patients. A comprehensive overview is given of existing hormonal therapies, including oral contraceptives, intrauterine devices, transdermal and subcutaneous estradiol patches, gnRH-agonists, oral testosterone, and 5α reductase inhibitors. The authors discuss their effectiveness and risks, noting their suitability for different patient profiles. Next, novel evolving hormonal treatments, such as oxytocin and prolactin, are explored. Lastly, the authors cover hormonal conditions associated with migraine, such as polycystic ovary syndrome, endometriosis, and transgender persons receiving gender affirming hormone therapy, aiming to provide more personalized and effective solutions for migraine management. Expert opinion: Rigorous research into both existing and new hormonal targets, as well as the underlying pathophysiology, is needed to support a tailored approach in migraine treatment, in an ongoing effort to alleviate the impact of migraine on individuals and society.</p

Case reports: Could sexual dysfunction in women with migraine be a side effect of CGRP inhibition?

BACKGROUND: The development and approval of antibodies targeting calcitonin gene-related peptide or its receptor mark a revolutionary era for preventive migraine treatment. Real-world evidence sheds light on rare, stigmatized or overlooked side effects of these drugs. One of these potential side effects is sexual dysfunction.CASE REPORTS: We present two cases of one 42-year-old and one 45-year-old female patient with chronic migraine who both reported sexual dysfunction as a possible side effect of treatment with galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide.DISCUSSION: As calcitonin gene-related peptide is involved in vaginal lubrication as well as genital sensation and swelling, inhibiting the calcitonin gene-related peptide pathway may lead to sexual dysfunction as a potential side effect.CONCLUSION: Sexual dysfunction in female migraine patients might be a rare and overlooked side effect of monoclonal antibodies targeting the calcitonin gene-related peptide pathway. Considering the discomfort and stigma surrounding both migraine and sexual dysfunction, we advocate for an open attitude and awareness among clinicians toward such side effects.</p

Considerations for hormonal therapy in migraine patients:a critical review of current practice

Introduction: Migraine, a neurovascular headache disorder, is a leading cause of disability worldwide. Within the multifaceted pathophysiology of migraine, hormonal fluctuations play an evident triggering and exacerbating role, pointing toward the need for identification and proper usage of both existing and new hormonal targets in migraine treatment. Areas covered: With a threefold higher incidence of migraine in women than in men, the authors delve into sex hormone-related events in migraine patients. A comprehensive overview is given of existing hormonal therapies, including oral contraceptives, intrauterine devices, transdermal and subcutaneous estradiol patches, gnRH-agonists, oral testosterone, and 5α reductase inhibitors. The authors discuss their effectiveness and risks, noting their suitability for different patient profiles. Next, novel evolving hormonal treatments, such as oxytocin and prolactin, are explored. Lastly, the authors cover hormonal conditions associated with migraine, such as polycystic ovary syndrome, endometriosis, and transgender persons receiving gender affirming hormone therapy, aiming to provide more personalized and effective solutions for migraine management. Expert opinion: Rigorous research into both existing and new hormonal targets, as well as the underlying pathophysiology, is needed to support a tailored approach in migraine treatment, in an ongoing effort to alleviate the impact of migraine on individuals and society.</p

Revisiting dose-finding of monoclonal antibodies in migraine

Migraine is a debilitating disorder, and while the introduction of monoclonal antibodies (mAbs) has led to efficacious and tolerable responses, a substantial number of patients are so-called “non-responders”. We introduce reasons for this insufficient response, including insufficient blockade of Calcitonin Gene-Related Peptide (CGRP) or its receptor. We present a clinical case, i.e. a female migraine patient who mistakenly administered supratherapeutic (three-fold higher) doses of erenumab leading to more efficacious clinical responses without any side-effects. This example illustrates that the initial dosages might have been too low, resulting in a remaining undesired increased effect of CGRP. While a capsaicin forearm model has repeatedly been used to evaluate the pharmacokinetic-pharmacodynamic relationship of mAbs, we provide directions to revisit or reconsider dose-finding and dose-ranging of these drugs. These directions include (i) refinement and application of a capsaicin forehead model (instead of a forearm model) to study trigeminovascular activity and improve dosing, and (ii) reconsideration of trial populations. Indeed, the dose-finding studies were mainly performed in relatively young and normal-weight males, while most phase III/IV trials are marked by a high female-to-male ratio, mainly consisting of overweight to obese females. Considering these aspects in future trials could optimize healthcare for a larger proportion of migraine patients.</p

Serotonergic Modulation of Neurovascular Transmission:A Focus on Prejunctional 5-HT Receptors/Mechanisms

5-Hydroxytryptamine (5-HT), or serotonin, plays a crucial role as a neuromodulator and/or neurotransmitter of several nervous system functions. Its actions are complex, and depend on multiple factors, including the type of effector or receptor activated. Briefly, 5-HT can activate: (i) metabotropic (G-protein-coupled) receptors to promote inhibition (5-HT1, 5-HT5) or activation (5-HT4, 5-HT6, 5-HT7) of adenylate cyclase, as well as activation (5-HT2) of phospholipase C; and (ii) ionotropic receptor (5-HT3), a ligand-gated Na+/K+ channel. Regarding blood pressure regulation (and beyond the intricacy of central 5-HT effects), this monoamine also exerts direct postjunctional (on vascular smooth muscle and endothelium) or indirect prejunctional (on autonomic and sensory perivascular nerves) effects. At the prejunctional level, 5-HT can facilitate or preclude the release of autonomic (e.g., noradrenaline and acetylcholine) or sensory (e.g., calcitonin gene-related peptide) neurotransmitters facilitating hypertensive or hypotensive effects. Hence, we cannot formulate a specific impact of 5-HT on blood pressure level, since an increase or decrease in neurotransmitter release would be favoured, depending on the type of prejunctional receptor involved. This review summarizes and discusses the current knowledge on the prejunctional mechanisms involved in blood pressure regulation by 5-HT and its impact on some vascular-related diseases.</p

Case reports: Could sexual dysfunction in women with migraine be a side effect of CGRP inhibition?

BACKGROUND: The development and approval of antibodies targeting calcitonin gene-related peptide or its receptor mark a revolutionary era for preventive migraine treatment. Real-world evidence sheds light on rare, stigmatized or overlooked side effects of these drugs. One of these potential side effects is sexual dysfunction.CASE REPORTS: We present two cases of one 42-year-old and one 45-year-old female patient with chronic migraine who both reported sexual dysfunction as a possible side effect of treatment with galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide.DISCUSSION: As calcitonin gene-related peptide is involved in vaginal lubrication as well as genital sensation and swelling, inhibiting the calcitonin gene-related peptide pathway may lead to sexual dysfunction as a potential side effect.CONCLUSION: Sexual dysfunction in female migraine patients might be a rare and overlooked side effect of monoclonal antibodies targeting the calcitonin gene-related peptide pathway. Considering the discomfort and stigma surrounding both migraine and sexual dysfunction, we advocate for an open attitude and awareness among clinicians toward such side effects.</p

Comparison of gepant effects at therapeutic plasma concentrations:connecting pharmacodynamics and pharmacokinetics

Background: Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance. Methods: We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research. Results: We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations. Conclusions: The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients.</p

Blocking the CGRP Receptor:Differences across Human Vascular Beds

Multiple drugs targeting the calcitonin gene-related peptide (CGRP) receptor have been developed for the treatment of migraine. Here, the effect of the small-molecule CGRP receptor antagonist zavegepant (0.1 nM–1 µM) on CGRP-induced relaxation in isolated human coronary arteries (HCAs) was investigated. A Schild plot was constructed and a pA2 value was calculated to determine the potency of zavegepant. The potency and Schild plot slopes of atogepant, olcegepant, rimegepant, telcagepant, ubrogepant and zavegepant in HCAs and human middle meningeal arteries (HMMAs), obtained from our earlier studies, were compared. Zavegepant shifted the concentration–response curve to CGRP in HCAs. The corresponding Schild plot slope was not different from unity, resulting in a pA2 value of 9.92 ± 0.24. No potency difference between HCAs and HMMAs was observed. Interestingly, olcegepant, atogepant and rimegepant, with a Schild plot slope &lt; 1 in HCAs, were all &gt;1 log unit more potent in HMMAs than in HCAs, while telcagepant, ubrogepant and zavegepant, with a Schild plot slope not different from unity, showed similar (&lt;1 log difference) potency across both tissues. As a Schild plot slope &lt; 1 may point to the involvement of multiple receptors, it is important to further identify the receptors involved in the relaxation to CGRP in HCAs, which may be used to improve the cardiovascular safety of future antimigraine drugs.</p

Pharmacological Nature of the Purinergic P2Y Receptor Subtypes That Participate in the Blood Pressure Changes Produced by ADPβS in Rats

Purine nucleosides (adenosine) and nucleotides such as adenosine mono/di/triphosphate (AMP/ADP/ATP) may produce complex cardiovascular responses. For example, adenosine-5′-(β-thio)-diphosphate (ADPβS; a stable synthetic analogue of ADP) can induce vasodilatation/vasodepressor responses by endothelium-dependent and independent mechanisms involving purinergic P2Y receptors; however, the specific subtypes participating in these responses remain unknown. Therefore, this study investigated the receptor subtypes mediating the blood pressure changes induced by intravenous bolus of ADPβS in male Wistar rats in the absence and presence of central mechanisms with the antagonists MRS2500 (P2Y1), PSB0739 (P2Y12), and MRS2211 (P2Y13). For this purpose, 120 rats were divided into 60 anaesthetised rats and 60 pithed rats, and further subdivided into four groups (n = 30 each), namely: (a) anaesthetised rats, (b) anaesthetised rats with bilateral vagotomy, (c) pithed rats, and (d) pithed rats continuously infused (intravenously) with methoxamine (an α1-adrenergic agonist that restores systemic vascular tone). We observed, in all four groups, that the immediate decreases in diastolic blood pressure produced by ADPβS were exclusively mediated by peripheral activation of P2Y1 receptors. Nevertheless, the subsequent increases in systolic blood pressure elicited by ADPβS in pithed rats infused with methoxamine probably involved peripheral activation of P2Y1, P2Y12, and P2Y13 receptors.</p