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

Sex hormones, including estrogen, progesterone, and testosterone, play a multifaceted role in migraine pathophysiology [ 21 ]. MacGregor et al. showed that in the 5 days preceding menstruation, the likelihood of suffering a migraine attack was increased by 25% [ 22 ]. This climbed up to 71% in the 2 days preceding menstruation. On the first day of menstruation and 5 days after the risk was increased by about 100%. Figure 1 depicts serum levels of sex hormones and their effect on the endometrium over the course of the menstrual cycle, as well as their concurrence with fluctuations in incidence of migraine attacks in women with menstrual migraine. Figure 1. Menstrual cycle and migraine frequency. In this figure, serum levels of hormones and their effect on the endometrium over the course of the menstrual cycle are depicted, as well as the concurrence of fluctuations in the incidence of migraine attacks in women with menstrual migraine. Lasting around 28 days, the cycle starts with the release of FSH, stimulating the growth of ovarian follicles. The maturation of these follicles leads to an increasing production of estradiol, which triggers a surge in LH and causes ovulation. After ovulation, the ruptured follicle transforms into the corpus luteum which produces progesterone and prepares the endometrium for possible fertilization. If fertilization does not occur, the corpus luteum breaks down progesterone and estradiol levels drop, which triggers menstruation and the start of a new menstrual cycle [ 23 ]. The decline of estradiol, also referred to as estradiol-withdrawal, is also thought to precipitate a migraine attack without aura in women with menstrual migraine [ 24 ]. The figure is based on the data from Martin et al. [ 25 ] and MacGregor et al. [ 26 ] and was created using BioRender. Menstrual cycle and migraine frequency. In this figure, serum levels of hormones and their effect on the endometrium over the course of the menstrual cycle are depicted, as well as the concurrence of fluctuations in the incidence of migraine attacks in women with menstrual migraine. Lasting around 28 days, the cycle starts with the release of FSH, stimulating the growth of ovarian follicles. The maturation of these follicles leads to an increasing production of estradiol, which triggers a surge in LH and causes ovulation. After ovulation, the ruptured follicle transforms into the corpus luteum which produces progesterone and prepares the endometrium for possible fertilization. If fertilization does not occur, the corpus luteum breaks down progesterone and estradiol levels drop, which triggers menstruation and the start of a new menstrual cycle [ 23 ]. The decline of estradiol, also referred to as estradiol-withdrawal, is also thought to precipitate a migraine attack without aura in women with menstrual migraine [ 24 ]. The figure is based on the data from Martin et al. [ 25 ] and MacGregor et al. [ 26 ] and was created using BioRender. The key role of sex hormones in migraine can also be comprehended by analyzing how different life events influence migraine frequency. Before puberty, differences between the activity of sex hormones are less pronounced, and there is equal prevalence of migraine in both sexes [ 27 ]. After menarche, there is a sharp increase in migraine prevalence in women, leading to a shift in male-to-female ratio [ 28 ]. When it comes to pregnancy, about 50–75% of women with migraine experience a reduction in migraine attacks and pain intensity, especially in the second and third trimesters. While the headache frequency can increase in the postpartum period, breastfeeding seems to have a protective effect [ 29 ]. When leaving the fertile years and moving on to menopause, the perimenopausal period is associated with another increase in frequency, pain severity, and treatment response of migraine while experiencing a decline in those factors after natural menopause [ 30 ]. The entirety of mechanisms involving different hormones have not been fully elucidated. However, several studies have shown that fluctuating levels of different sex hormones can either trigger a migraine attack or have a protective influence [ 31 ]. The evidence concerning the role of several hormones will be explained shortly. A key theory involving hormonal influences in migraine is the ‘estrogen withdrawal hypothesis,’ stating that changes in serum estradiol levels, especially drops in estradiol during the luteal phase just before menstruation, triggers menstrual migraines in susceptible women [ 24 , 26 , 31 ]. This increase in the occurrence of migraine attacks is most likely to be linked to an interaction between sex hormone fluctuations and CGRP, as demonstrated by animal and human preclinical models [ 32 ]. Fluctuations of mainly estrogen modulate CGRP release in the peripheral and central trigeminovascular system, as reviewed by Labastida-Ramérez et al. [ 32 ]. Valdemaarson et al. studied plasma levels of CGRP in a healthy population and found significantly higher levels in females than in males, while women using contraceptives had significantly higher levels than women without [ 33 ]. The correlation between estrogen levels and CGRP levels during menstruation was also demonstrated by Raffaelli et al. They measured CGRP levels in plasma and tear fluid during menstruation (i.e. when serum estrogen levels are low) and showed that women suffering from migraine had elevated CGRP levels compared to healthy controls [ 34 ]. An observational study found that the rate of decline of conjugated urinary estrogens in migraine patients in the late luteal phase is faster compared to controls, while there was no difference in the rate of estrogen withdrawal after the periovulatory peak. Additionally, the authors demonstrated that within migraine patients, the rate of conjugated urinary estrogens decline remained consistent, regardless of whether a headache occurred during the menstrual cycle. Researchers then proposed a ‘two-hit’ hypothesis, indicating that the faster estrogen decline could be an endogenous feature of women with migraine, leading to neuroendocrine vulnerability which may facilitate migraine attacks by common triggers, like alcohol or stress [ 35 ]. Ibrahimi et al. performed a case–control study to examine the dermal blood flow responses to capsaicin and electrical stimulation on days 1–2 and 19–21 of the cycle in women suffering from menstrual migraine. They found that in the control group, responses to capsaicin were higher on days 1–2 than on days 19–21, a finding which was not detected in the migraine group (where responses were similar over the cycle), leading to the hypothesis of reduced trigeminovascular cyclicity in women suffering from menstrual migraine. Interestingly, they also found that estradiol serum levels on days 19–21 were higher in healthy controls (75 ± 8 pg/mL) than in women with menstrually related migraine (52 ± 4 pg/mL) [ 36 ]. Serum estradiol does not only play a key role in migraine in females but may also be involved in pathophysiology of male migraineurs. Van Oosterhout et al. measured the 17β-estradiol and calculated free testosterone in serum of male migraineurs and healthy controls. They found that the migraine group had significantly higher interictal 17β-estradiol (96.8 ± 6.1 vs 69.1 ± 5.6 pmol/L) levels and a lower 17β-estradiol/free testosterone ratio (3.9 ± 0.4 vs 5.0 ± 0.3) compared to controls [ 37 ]. Pringsheim et al. [ 38 ] examined the effect of antiandrogens and estrogens used by male to female transsexuals. They included 50 transsexuals, each of whom had to fill out a questionnaire consisting of 8 questions regarding the characteristics of their headaches. The results showed that the prevalence of migraine in the male to female transsexuals was similar to the prevalence expected for genetic females. Moreover, 54% of those suffering from migraine reported visual aura, a phenomenon which could disappear after reducing the dosage of estrogen [ 39 ]. Progesterone is believed to have a protective effect against migraine attacks by modulating nociception and downregulating estrogen receptors [ 40 , 41 ]. Progesterone, which is mainly active during the luteal phase [ 42 ], is believed to hold a protective role in migraine. Similar to estrogen, progesterone plasma levels decrease before menstruation [ 43 ]. However, two studies [ 44 , 45 ] assessed the role of withdrawal of progesterone and estrogen, clearly showing the worsening effect of estradiol withdrawal, while the withdrawal of progesterone did not have any worsening effect on the course of migraine. While the worsening effect could not be demonstrated, a possible pathway of progesterone being protective against menstrual migraine attacks was found. This might be due to reducing activation in the trigeminal nucleus caudalis and causing an antinociceptive effect [ 40 ]. Additionally, the neurosteroid allopregnanolone, which is an active metabolite of progesterone and acts as a positive modulator of Gamma-Aminobutyric Acid (GABA) receptors, has shown antinociceptive effects in animal studies [ 43 , 46 , 47 ]. This brought authors to consider the hypothesis that progesterone and its metabolite, allopregnanolone, hold the potential to be beneficial in migraine by modulating pain perception. However, the administration of progesterone does not prevent migraine attacks [ 44 ], leading to the opinion of progesterone not being a major factor in triggering these attacks [ 43 ]. The role of the neuroactive steroid testosterone in the modulation of migraine headaches is less well understood compared to estrogen and progesterone, although it may play a role in cerebral blood flow and serotonergic tone [ 48 ]. Testosterone has been shown to have an endothelium-independent vasodilatory role in preclinical studies as reviewed by Herring et al. [ 49 ]. A recent study found that the prenatal estrogen–testosterone balance might be a risk factor for migraine in adults [ 50 ]. Females suffering from migraine were allegedly exposed to higher testosterone levels relative to estrogen in the prenatal period, while males suffering from migraine were presumably exposed to higher estrogen levels relative to testosterone, during their prenatal period. In mice, it has been shown that the administration of testosterone plays an important role in the suppression of cortical spreading depression in mice with familial hemiplegic migraine [ 51 ]. In addition, in healthy men, testosterone – but not estradiol – has been demonstrated to negatively correlate with serotonin 4 receptor levels [ 52 ]. Further, a small study consisting of 15 postmenopausal women not taking estrogens found no significant differences in serum levels of androstenedione, total testosterone, and free testosterone between those with migraine and healthy controls [ 53 ]. In addition, Shields et al. measured the testosterone levels in men with chronic migraine. They found that men suffering from chronic migraine had significantly lower mean testosterone levels than age-matched controls (322 ng/dL vs. 384 ng/dL) [ 54 ]. There is no evidence regarding the role of gonadotropin releasing hormone (GnRH) in the course of migraine. However, the suppression of gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) due to the administration of large doses of GnRH appears to have beneficial effects on migraine severity, as discussed in the treatment section [ 55 ]. The hypothalamic-pituitary-ovarian axis describes a tight endocrine system that plays a central role in regulating female reproductive function [ 56 ]. The pulsatile release of GnRH leads to the secretion of FSH and LH from the pituitary gland which subsequently causes the release of estrogen and progesterone from the ovaries. Over the course of the menstrual cycle, the pulsatile secretion of GnRH results in different serum levels of the hormones involved, including LH and FSH [ 57 ]. The above mentioned system and its role in migraine were examined by Facchinetti et al., who measured LH, FSH, prolactin, estradiol, and progesterone before and after the prophylactic treatment of dihydroergotamine in women with perimenstrual migraine. The plasma levels of LH, FSH, and prolactin were similar between women with migraine and controls and were unaffected by the prophylactic treatment with dihydroergotamine. However, women with migraine showed reduced progesterone levels over the entire course of the luteal phase, which was accompanied by higher estradiol levels, which lead to a progesterone/estradiol ratio which significantly disturbed ovarian steroid secretion. Based on these data, it can be inferred that there is an impairment of ovarian secretion in the context of perimenstrual migraine [ 58 ].

Migraine is a prevalent neurovascular disorder characterized by recurrent moderate-to-severe headache attacks, with an estimated global prevalence of 15% [ 1 , 2 ]. The World Health Organization ranks migraine as the second highest cause of disability in the world, especially in women under the age of 50 [ 3 ]. A specific subtype of migraine attacks occurring around menstruation with a close link to hormones is perimenstrual migraine episodes. Perimenstrual migraine affects about 20–25% of females with migraine in the general population, and 22–70% of patients presenting to headache clinics [ 4 ]. Perimenstrual migraine is typically characterized by a higher severity and frequency of attacks and more difficulty to treat, compared to hormone-independent migraine episodes [ 5 ]. In women diagnosed with menstrual migraine, menstrually related migraine or pure menstrual migraine should be distinguished. About two-thirds of women with migraine experience menstrually related migraine [ 6 , 7 ], where attacks tend to occur around menstruation but are also present at other times of the cycle. However, pure menstrual migraine, in which migraine attacks occur exclusively around menstruation, is a rare condition, affecting less than 1% of women with migraine. Hence, there have been doubts raised regarding the clinical significance of discerning between these subtypes [ 6 , 7 ]. Although the multifaceted pathophysiology of migraine is only partially understood, the initiation of migrainecl attacks is attributed to the activation of the trigeminovascular system. This leads to the release of neuropeptides, in particular calcitonin gene-related peptide (CGRP), causing vasodilation in the meningeal blood vessels and activation of nociceptive transmission [ 8 , 9 ]. For menstrually related migraine, two main triggering mediators of these mechanisms have been identified: estrogen withdrawal and prostaglandin release, which will both be discussed later on. The hormonal treatments available show unsatisfactory results in many patients, pointing out the requirement of future targets. Moreover, as societal diversification advances (e.g. transgender persons with migraine, patients with comorbidities) increase the complexity of the patient population and the urge for safe and efficacious treatments for these populations is becoming more and more important. Several overviews have already been published about hormonal treatments for migraine [ 10–20 ], mainly focusing on contraceptives and hormone replacement therapies, while missing out on further options like testosterone or GnRH-agonists. This review aims to present an overview on the relationship between migraine and sex hormones and to provide a summary of current evidence concerning efficacy and safety of all hormonal treatments available with a focus on clinical studies. Another focus will be on migraine treatment in certain subpopulations with a special hormonal landscape like transgender persons or women suffering from endometriosis or polycystic ovary syndrome. While this review will also provide a glimpse into future therapeutic options for migraine, it is of particular importance to emphasize the relevance of further research and rigorous studies on this topic. Because current therapy options often show limited effectiveness, an extended knowledge about the pathophysiology and pharmacological aspects of this disorder will be crucial to improve the quality of life of those affected.

Migraine is a complex and debilitating neurovascular disorder, in which finding the right treatment pattern is not only challenging for clinicians but also crucial for the patient’s quality of life. In the last years, much attention of research has been given to the CGRP(−receptor) monoclonal antibodies and gepants, which undoubtedly enhance the quality of life for many patients. However, the treatment of menstrual migraine still poses specific challenges, being a more resistant subtype that is less responsive to prophylactic pharmacological treatments [ 147 ]. Results of a recent study on the effect of CGRP(−receptor) monoclonal antibodies in 40 patients with menstrual-related migraine and three or more previous treatment failures further confirmed this [ 148 ]. Besides a significant reduction of median menstrual migraine frequency, pain intensity, and attack duration, they showed that menstrual migraine episodes had a slightly less treatment response compared to the non-menstrual migraine episodes (72.4% reduction vs. 60% reduction) [ 148 ]. Notably, post-hoc analyses of a real-world study showed no differences in treatment responses between perimenstrual and nonperimenstrual migraine days in menstruating women using erenumab or fremanezumab, although the treatment effect was greater in women compared to men [ 149 ]. The difficulty of treatment in these patients, due to different treatment responses is shown in our review, and the data presented draws a difficult picture. As there are only very limited data available, and quality of evidence is weak due to missing out on randomized controlled trials, studies with sufficient power and standardized parameters to ensure standardized assessment of the treatment effects, recommendations can only be given with reservation. This proves that the demand for future studies and future therapeutic options for menstrual migraine is high. Upcoming studies should evaluate efficacy and safety of treatment options (e.g. oxytocin) by using comparable and objective end points like monthly migraine days and specific pain scores [ 21 ]. Moreover, more randomized controlled trials consisting of a proper design and cohort studies with adequate power are needed. As our review has presented studies with conflicting results, it once again pointed out the importance of individual therapy considerations and personalized medicine. As we have seen in treatment forms like CGRP(−receptor) or especially gepants, pharmacokinetic and pharmacodynamic processes play a pivotal role in treatment responses, efficiency, and side-effects in individual patients. These processes are influenced by patient characteristics like age, sex, gender, and ethnic background – underlying the importance of adhering to an intersectional framework when developing individualized treatment recommendations [ 150 , 151 ]. While the available treatments very often show unsatisfying results, oxytocin and prolactin show potential as therapeutic options in the future. Being currently researched, smaller studies have already indicated that they could have beneficial effects on migraine and, therefore, could represent new targets to tackle the migraine burden [ 152 ]. Exploring future treatment options for migraine is also imperative due to the need to mitigate potential long-term cardiovascular risks associated with CGRP(−receptor) targeted antibodies [ 153 ], and the combined hormonal treatments available [ 87 ]. However, this should not detain researchers from examining the effect of already existing therapies and off-label use of hormonal therapies on the course of migraine. As an example, aromatase inhibitors – which suppress estrogen serum levels and are currently approved as a treatment of (hormone-receptor positive) breast cancer in premenopausal (in addition to a GnrRH analog) and postmenopausal women and in men and gynecomastia in men [ 154 ] – might theoretically be an attractive treatment option in men with chronic migraine. Indeed, these individuals exhibit higher serum estradiol levels and a lower estradiol/free testosterone ratio [ 37 ], suggesting a hormonal influence of estrogen in particular. In addition, although unsupported by actual published data, the aforementioned pilot study of Glaser et al. [ 30 ] mentions that many premenopausal patients were found to have a larger headache relief with the addition of the aromatase inhibitor anastrozole delivered in combination with testosterone. Therefore, a further exploration of the use of aromatase inhibitors, especially in those who suffer from comorbidities (e.g. breast cancer), could potentially serve as a valuable agent in the field. Studying their clinical effects could, therefore, provide additional insights into the modulating role of estrogen levels and their impact on migraine frequency and severity in both male and female migraine patients. Another priority of the future will be to conduct rigorous research on the pathophysiology of menstrual migraine to understand the interaction between different sex hormones while disentangling their individual contribution. A translational study found reduced trigeminovascular cyclicity in women with menstrual migraine, with the trigeminovascular activity being reduced during the first days of the cycle, compared to healthy controls [ 36 ]. This is indeed notable, as the higher CGRP concentrations in the blood and tear fluid during migraine attacks would lead to the assumption of higher activity during these migraine likely days [ 34 ]. These results are exemplary for mechanisms not being fully understood, while understanding the pathophysiological backgrounds would enable researchers to detect more specific targets. In summary, migraine, a complex condition, is frequently accompanied by comorbidities, emphasizing the imperative for personalized medicine. This approach entails a deep comprehension of a patient’s unique hormonal sensitivities, medical history and comorbidities, as well as risk profile. Coupled with rigorous research and the advancement of novel hormonal targets, personalized medicine holds the key to pave the way to a migraine-less future.

While current hormonal treatments for migraine offer relief for some, a comprehensive understanding of migraine’s multifaceted nature continues to drive innovation in therapeutic strategies. In this section, we will focus particularly on the hypothalamic neuropeptide oxytocin and the pituitary-derived hormone prolactin, as these hormones have been reported to play a modulating role in migraine, contributing to its sex-dimorphism, and offer potential therapies targeting these hormones or their receptors. Oxytocin is of interest in hormone-related migraine, as it can suppress migraine attacks [ 104 ]. Oxytocin fibers and oxytocin receptors have been identified in several brain regions associated with migraine and nociceptive processing [ 105 , 106 ]. Substantial circumstantial evidence points to oxytocin playing a role in hormonal migraine pathophysiology. For instance, Amico et al. [ 107 ] found that in women chronically receiving estrogen as an oral contraceptive, oxytocin levels were enhanced. Acute ingestion of estrogen caused an increase in the level of oxytocin in plasma by 12 hours. Additionally, the perimenstrual drop in oxytocin levels in humans parallels that of estrogen and could contribute to the withdrawal trigger for menstrual attacks [ 43 ]. Similarly, the level of circulating oxytocin also increases over the course of pregnancy, while simultaneously the frequency of migraine headaches decreases [ 108 ]. Finally, breastfeeding migraine patients have higher circulating levels of oxytocin compared to migraineurs that bottle feed their baby [ 109 ] and demonstrate a slower rate of postpartum migraine recurrence [ 110 ]. Krause et al. [ 43 ] propose that estrogen acts throughout the migraine-related circuits to increase thresholds and suppress initiation of an attack, either directly or indirectly via oxytocin or other estrogen-regulated signaling molecules. Hence, an appropriately timed treatment with oxytocin agonists could form a new approach to therapy for hormone related-migraine. Oxytocin in the systemic blood circulation, however, has difficulty crossing the blood-brain-barrier, necessitating routes other than oral or parenteral administration to reach the central nervous system [ 111 ]. An example target is the trigeminal ganglia, as in vitro experiments demonstrated that trigeminal ganglia neurons possess oxytocin receptors and are inhibited by oxytocin. Furthermore, most of these same neurons contain CGRP, the release of which is inhibited by oxytocin [ 112 ]. Decreasing the excitability of trigeminal neurons with oxytocin could lead to decreasing the probability of triggering a migraine attack. One way of targeting trigeminal ganglia is via the nasal route, which is also more user-friendly compared to oral administration when regarding symptoms of nausea in migraine. After demonstrating that activation of central trigeminal nerve nuclei in rodents can be attenuated by intranasal oxytocin, Tzabazis et al. subsequently performed several clinical studies with intranasal oxytocin in migraine patients [ 104 ]: A clinical pilot double-blind, placebo-controlled, single-dose study did not show a statistically significant difference in reduction of pain intensity at 2 h after administration of intranasal oxytocin compared to placebo in low-frequency migraineurs [ 104 ]. Another pilot trial was performed to test whether, in the presence of chronic migraine and thus higher levels of neuro-inflammation, analgesic efficacy of intranasal oxytocin would be increased. In this double-blind, placebo-controlled, single-dose study, patients were randomized to receive either 32 IU of intranasal oxytocin ( n  = 22) or matched placebo intranasal spray ( n  = 18). A significant difference was demonstrated 4 hours after dosing; however, there was no significant difference in the more acute measurement 2 hours after dosing. Most notable, however, 24 hours after dosing, efficacy was substantially stronger in chronic migraine patients who had not taken anti-inflammatory medication within 24 hours of oxytocin dosing, compared to participants who did take anti-inflammatory medication within 24 hours of dosing. A follow-on open-label study examining effects of 1 month of intranasal oxytocin dosing did show a reduction in pain, but a more impressive decrease in the frequency of headaches in both chronic and high frequency episodic migraineurs [ 104 ]. Lastly, a multisite double-blind, placebo-controlled, migraine prophylaxis trial was performed in Chile, Australia, and New Zealand. In total, 218 patients, including 61 high frequency episodic; 56 chronic migraineurs, were given intranasal oxytocin ‘as needed’ for 56 days, after a baseline period of 28 days. The results of this study, though not meeting its primary endpoint due to a high placebo rate in one of the countries, did show that the vast majority of patients experienced a profound increase in the number of weeks wherein no headaches were reported and so provided a clear justification for further research [ 104 ]. All in all, the above results are highly suggestive of intranasal oxytocin being effective in chronic migraine prophylaxis. More well-controlled and well-designed clinical trials with a focus on different hormonal states of patients are warranted, as well as back translational studies to understand the physiological effects of intranasal oxytocin. Prolactin, which has a crucial role in controlling the hypothalamus-pituitary-gonadal (HPG) axis, seems to be involved in signaling mechanisms underlying migraine. A systematic review [ 113 ] investigated the role of prolactin and its receptors in headache and migraine, of which the following studies examined the serum levels of prolactin in different groups of migraine patients: A case–control study showed that prolactin levels were higher in 20 migraine without aura patients compared to 20 healthy controls on the second day of the menstrual cycle [ 114 ]; serum prolactin levels were higher in women with chronic migraine compared to women with episodic migraine [ 115 ]; no difference in serum prolactin levels in 50 female migraine patients (with and without aura) during interictal period compared to 25 age-matched healthy female controls [ 116 ]. Contrastingly, Masoud and Fakharian [ 117 ] reported that serum prolactin levels from 37 migraine patients during migraine attacks were significantly lower compared to not age-matched 37 healthy controls. The authors did not report if the healthy controls had any headache during prolactin measurement and did not compare ictal to interictal prolactin levels in migraine patients. Regarding prolactin and migraine treatment, dopamine agonists including bromocriptine and carbidopa/levodopa have reportedly been effective in managing migraines supposedly triggered by elevated prolactin levels by inhibiting prolactin release. However, only limited evidence is yet available to support this. Hartman et al. [ 118 ] published a case-report of a 39-year-old male, with a 27-year history of chronic severe migraine, who received an incidental diagnosis of a prolactin-secreting pituitary microadenoma. Treatment of the microadenoma with bromocriptine provided complete and lasting resolution of the migraine as well, suggesting a possible etiologic relationship and prospect regarding dopamine agonist treatment in such cases of migraine influenced by prolactin. Additionally, in a study conducted by Cavestro and colleagues [ 119 ], it was demonstrated that out of 27 patients (comprising one man and 26 women) suffering from chronic migraine, seven women exhibited elevated serum prolactin levels compared to reference values. Notably, these individuals experienced an improvement in their headache symptoms, and their migraines transitioned to an episodic pattern following treatment with the dopamine agonist cabergoline. However, there have been two cases where the administration of dopamine agonists resulted in worsening of headache [ 120 ], leaving a lingering debate in this area. Overall, considerable evidence supports the link between elevated levels of endogenous prolactin, its receptors, and the increased incidence and severity of migraine. However, the exact underlying causative mechanisms and the difference in responses between episodic versus chronic migraine remain to be further elucidated [ 121 ]. Additional randomized and placebo-controlled clinical trials focusing on prolactin signaling are necessary to provide further insight into the role of prolactin in initiating migraine attacks and its future position in migraine treatment. In light of this, and in order to advance toward a potential appropriately timed treatment with either existing or potential new drugs oxytocin agonists in hormone related-migraine, the effect of periovulatory administration of such migraine targeted drug treatments can be studied in a noninvasive human forehead model, developed and validated by Ibrahimi et al. [ 122 ]. The model uses a laser device as imaging technique to study local trigeminovascular effects in the forehead skin of (potential) antimigraine drugs, providing proof of target engagement in phase I clinical trials and potential guiding dose selection for phase II clinical trials. Periovulatory administration was chosen because of the ovulation coinciding with the start of the ‘estrogen withdrawal’ phase of the menstrual cycle. A secondary objective of this study is to investigate how the trigeminovascular dermal blood flow response to migraine drugs oxytocin is related to serum biomarkers, such as CGRP, serum oxytocin, and sex steroids in the study participants, further elucidating the complex interactions of several hormones in migraine.

Another challenge of the future will be dealing with patients who do not only suffer from menstrual-related migraine but also other hormonal disturbances or changes, such as patients with endometriosis, polycystic ovary syndrome (PCOS), or transgender persons receiving gender affirming hormone therapy. Glintborg et al. found a twofold risk for migraine in women with PCOS compared to controls [ 123 ]. However, another study consisting of 133 women with PCOS found no correlation between PCOS and the presence of migraine [ 124 ]. Some authors speculate that the higher prevalence of migraine may be due to sleep disturbances and reduced REM sleep time in PCOS [ 125 ]. What makes the comorbidity of migraine and PCOS especially challenging is that not only women suffering from PCOS have a two times increased risk of stroke and thrombosis [ 123 ] but also the first-line treatment for PCOS, combined oral contraceptives, is associated with a worsening in migraine and a higher risk of stroke [ 126 ]. Therefore, we encourage the use of non-hormonal treatments for women with PCOS and migraine, such as lifestyle changes and metformin, which have shown to be effective [ 127 ]. Endometriosis is significantly associated with an increased risk of migraine headache, according to a recent meta-analysis, which included 287.174 women (OR 1.56 95% CI 1.21–1.90) [ 128 ]. Some biochemicals such as prostaglandins, nitrite oxide, and estrogen are involved in the pathophysiology of both diseases [ 128 ]. Estrogen seems to play a central role in the genetic link underlying the comorbidity of endometriosis and migraine. Women who share overlapping estrogen receptor polymorphisms may find greater relief from their symptoms through continuous progestin-based estrogen suppression. Several studies show that treatment with progestin-only options has a beneficial effect on both migraine and endometriosis, as reviewed by van der Vaart et al. [ 129 ], whereas combined oral contraceptives often worsen migraine symptoms [ 10 ]. Identifying the co-occurrence of migraine and endometriosis can therefore optimize hormonal treatment and we recommend treating migraine in women with endometriosis with oral progestins or levonorgestrel intrauterine system as firstline treatment and GnRH-agonists after treatment failure [ 130 ]. Combined oral contraceptives or danazol are not recommended [ 131 ]. In transgender men (i.e. female at birth who identifies as a male), testosterone is used as a treatment to induce masculinizing changes, called gender affirming hormone therapy [ 132 ]. Finasteride, a 5α reductase inhibitor, is mostly used in benign prostatic hyperplasia by lowering serum levels of dihydrotestosterone [ 133 ]. In addition, it can be used in transgender women (i.e. male at birth who identifies as a female) for gender affirming hormone therapy [ 132 ]. In an anecdotal report published by Check and Cohen, the administration of 5 mg finasteride, a 5α reductase inhibitor, in a woman with chronic migraine, led to full disappearance of symptoms. After stopping the therapy due to dry eyes, the migraine returned [ 134 ]. No evidence was found regarding the risk of stroke or thromboembolic events. Another case report includes two transgender persons receiving gender-affirming hormone therapy, or more specifically, masculinizing hormone therapy with testosterone. They were both diagnosed with chronic migraine without aura. Headache severity was reported by using the Migraine Disability Assessment Score (MIDAS) and frequency by using monthly migraine days. After starting a therapy with injection of 200 mg/mL testosterone enanthate every 14 days, the first patient reported an improvement concerning the MIDAS from 46 to 5. The second patient was treated with 50 mg testosterone enanthate, later increased to 100 mg. Through this therapy, the patient reported a decrease in MIDAS from 17 to 8 and experienced a total cessation of menstrual bleeding [ 135 ]. A cross-sectional study on the effect of gender transition on primary headaches found that 50% of transgender males with migraine using gender affirming hormone therapy reported a decrease in migraine frequency, while 43.8% did not experience any change [ 136 ]. The use of testosterone as gender affirming hormone therapy in transgender men may be associated with a higher cardiometabolic risk. Two prospective studies found that after 1 year of use, subjects had higher levels of total cholesterol and LDL-cholesterol as well as lower levels of HDL-cholesterol [ 137 , 138 ]. These changes were confirmed by a meta analysis including 1500 transgender men, which also showed that a longer duration of use (>2 years) is associated with more undesirable effects on the lipid profile [ 139 ]. Additionally, some data suggest that gender affirming hormone therapy with testosterone could increase blood pressure; however, results are mixed and further studies are needed [ 132 ]. However, according to current evidence, the risk of stroke does not seem to be elevated by testosterone given as gender affirming hormone therapy, compared to cisgender men and women [ 140 ]. Breast cancer can be divided into four molecular subtypes, i.e. luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and basal-like breast cancer. About 60–70% belong to the luminal-like breast cancers, which are highly influenced by hormonal factors, expressing an estrogen receptor [ 141 ]. Migraine and breast cancer both have been shown to exhibit strong relations to the endocrine system. It has been a matter of discussion whether there is an association between migraine and breast cancer – a conflict further fueled by the fact that data on this topic are very heterogeneous. Several studies [ 142–144 ] have supported the hypothesis of migraine having beneficial effects by reducing the risk of breast cancer. However, a recent prospective study [ 145 ] found quite the opposite. Researchers detected a highly elevated prevalence of migraine in women with breast cancer, especially in the luminal-like subtypes. While the prevalence in the general population is about 17%, in this study 56% of participants were diagnosed with migraine, 76% of those with migraine without aura. Moreover, more than 50% of study participants suffering from migraine reported it to be menstrually related. Interestingly, migraine patients had a higher risk of getting diagnosed at stage II or III breast cancer than at stage I. Further, while 365 of 440 women were treated with hormonal therapy, mostly aromatase inhibitors (47.4%) and tamoxifen (35.9%), researchers detected no influence of the hormonal therapy on the course of migraine. The discrepancies in data concerning the association between migraine and breast cancer might be explained by methodological differences between the studies. Only few studies used the ICHD classification for migraine diagnosis, opening the door to misdiagnosis and making a comparison of the outcomes of the different studies impossible. Another important aspect is the fluctuating character of migraine. Theoretically, it is possible that a woman may have suffered from migraine for years but is headache-free at the time of the breast cancer diagnosis, and therefore, it goes unnoticed as she reports not to have migraine. To date, there is no clear answer to how migraine and breast cancer influence each other and what the underlying mechanisms to that might be [ 146 ].

The abovementioned comorbidities illustrate the need for increased awareness that there is no one-size-fits-all approach in hormone-related migraine. While we did not conduct a systematic review and we do not claim that the current review includes all studies in the field, we observed that data are limited and suggestions for treatment are sometimes based on weak evidence and studies with limited power. Nonetheless, women with menstrual migraine are recommended to not use the standard regimen of the combined oral contraceptive pill, but rather an alternative regimen or use hormonal treatments based on progestins, like the progestin-only pill or the levonorgestrel intrauterine system. These recommendations should be underlined by further studies based on standardized parameters. Moreover, great effort should be put into the research on future therapeutic options, in order to enlarge the number of options. As societal diversification advances and the number of patients suffering from multiple comorbidities keeps growing, the migraine patient population will become increasingly complex. Therefore, a larger variety of safe, efficacious, and personalized treatment options are becoming increasingly important.

A search strategy was developed together with a librarian of the Erasmus MC Medical Library. The search strategy included the terms ‘migraine,’ ‘(peri)menopause,’ ‘hormone/hormonal treatment’ (exact search strings are included in the Appendix ) and focused on clinical studies. The following databases were searched on the 22 nd of June 2023 without time restriction: Medline ALL, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar (100 top-ranked). While no systematic selection of articles was performed, we additionally included references of retrieved articles.