Migraine is a severe neurovascular disorder of which the pathophysiology is not yet fully understood. Besides the role of inflammatory mediators that interact with the trigeminovascular system, cyclic fluctuations in sex steroid hormones are involved in the sex dimorphism of migraine attacks. In addition, the pituitary-derived hormone prolactin and the hypothalamic neuropeptide oxytocin have been reported to play a modulating role in migraine and contribute to its sex-dependent differences. The current narrative review explores the relationship between these two hormones and the pathophysiology of migraine. We describe the physiological role of prolactin and oxytocin, its relationship to migraine and pain, and potential therapies targeting these hormones or their receptors.In summary, oxytocin and prolactin are involved in nociception in opposite ways. Both operate at peripheral and central levels, however, prolactin has a pronociceptive effect, while oxytocin appears to have an antinociceptive effect. Therefore, migraine treatment targeting prolactin should aim to block its effects using prolactin receptor antagonists or monoclonal antibodies specifically acting at migraine-pain related structures. This action should be local in order to avoid a decrease in prolactin levels throughout the body and associated adverse effects. In contrast, treatment targeting oxytocin should enhance its signalling and antinociceptive effects, for example using intranasal administration of oxytocin, or possibly other oxytocin receptor agonists. Interestingly, the prolactin receptor and oxytocin receptor are co-localized with estrogen receptors as well as calcitonin gene-related peptide and its receptor, providing a positive perspective on the possibilities for an adequate pharmacological treatment of these nociceptive pathways. Nevertheless, many questions remain to be answered. More particularly, there is insufficient data on the role of sex hormones in men and the correct dosing according to sex differences, hormonal changes and comorbidities. The above remains a major challenge for future development.

1st Department of Neurology Eginition Hospital National and Kapodistrian University of Athens Athens Greece

Child Neuropsychiatry Unit Department Pro M 1 S E G D'Alessandro University of Palermo 90133 Palermo Italy

Department of Clinical and Molecular Medicine Sapienza University Rome Italy

Department of Diagnostic and Interventional Neuroradiology School of Medicine Klinikum rechts der Isar Technical University of Munich Ismaninger Str 22 81675 Munich Germany

Department of Neurology 401 Military Hospital of Athens Athens Greece

Department of Neurology City Hospital Ostrava Ostrava Czech Republic

Department of Neurology Clínica Universidad de Navarra Pamplona Spain

Department of Neurology Kartal Dr Lutfi Kirdar Research and Training Hospital Istanbul Turkey

Department of Neurology Medical University of Lublin Lublin Poland

Department of Pediatrics Dr von Hauner Children's Hospital LMU Hospital Division of Pediatric Neurology and Developmental Medicine Ludwig Maximilians Universität München Lindwurmstr 4 80337 Munich Germany

Division of Vascular Medicine and Pharmacology Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands

Doctoral School Medical University of Lublin Lublin Poland

Institute of Physiology and Pathophysiology Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

LMU Center for Children with Medical Complexity iSPZ Hauner Ludwig Maximilians Universität München Lindwurmstr 4 80337 Munich Germany

Neuroscience Section Department of Applied Clinical Sciences and Biotechnology University of L'Aquila 67100 L'Aquila Italy

Spine Health Unit Faculty of Physical Therapy and Rehabilitation Hacettepe University Ankara Turkey

TUM Neuroimaging Center Klinikum rechts der Isar Technical University of Munich Munich Germany

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