AccScience Publishing / AN / Online First / DOI: 10.36922/AN025220070
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REVIEW ARTICLE

The role of prolactin and oxytocin in migraine pathophysiology

Brooklyn A. Bradley1,2 ,  Deena E. Kuruvilla1*
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1 Brain Health Institute, Connecticut, United States of America
2 University of Connecticut School of Medicine, Farmington, Connecticut, United States of America
Advanced Neurology, 025220070 https://doi.org/10.36922/AN025220070
Received: 31 May 2025 | Revised: 17 August 2025 | Accepted: 19 August 2025 | Published online: 22 September 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

In recent years, researchers have turned their attention to prolactin and oxytocin, exploring how each might contribute differently to the biological processes that drive migraine. Both prolactin and oxytocin rise during lactation; however, they play distinct roles in the perception and regulation of pain. While prolactin is recognized as pronociceptive in migraine, oxytocin exhibits antinociceptive effects. The interactions between prolactin, oxytocin, and calcitonin gene-related peptide (CGRP) receptors are crucial for understanding migraine chronification and susceptibility, especially during periods of hormonal fluctuation. Prolactin and oxytocin exert opposing effects during migraine, enhancing trigeminal nociceptor sensitivity and promoting antinociceptive effects, respectively. Thus, prolactin and CGRP act synergistically to promote trigeminal sensitization, whereas oxytocin counteracts these effects by inhibiting CGRP release. Elevated serum prolactin and oxytocin levels may contribute to migraine pathophysiology through these mechanisms. Overall, the interactions between prolactin and oxytocin levels, their roles in migraine pathophysiology, and their effects on CGRP receptors highlight their potential as therapeutic targets. Therapeutic strategies that reduce prolactin signaling, enhance oxytocin signaling, or directly inhibit CGRP receptors may hold promise for future migraine treatments. Current treatment targets involving prolactin and oxytocin in migraine management remain investigational, and further research is necessary to identify efficacy, optimal dosing, patient selection, and potential sex differences.

Keywords
Prolactin
Oxytocin
Migraine disorders
Sex differences
Nociception
Calcitonin gene-related peptide
Funding
None.
Conflict of interest
Deena E. Kuruvilla has served on advisory boards, provided consultancy, and/or acted as a speaker or contributing author for AbbVie, Pfizer, Eli Lilly, and Cefaly Technology. Brooklyn A. Bradley has no competing interests to disclose.
References
  1. Al-Chalabi M, Bass AN, Alsalman I. Physiology, prolactin. In: StatPearls. StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507829 [Last accessed on 2025 May 29].

 

  1. Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: Structure, function, and regulation of secretion. Physiol Rev. 2000;80(4):1523-1631. doi: 10.1152/physrev.2000.80.4.1523

 

  1. Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. Prolactin (Prl) and its receptor: Actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev. 1998;19(3):225-268. doi: 10.1210/edrv.19.3.0334

 

  1. Augustine RA, Ladyman SR, Bouwer GT, et al. Prolactin regulation of oxytocin neurone activity in pregnancy and lactation. J Physiol. 2017;595(11):3591-3605. doi: 10.1113/JP273712

 

  1. Osilla EV, Patel P, Sharma S. Oxytocin. In: StatPearls. StatPearls Publishing; 2025. Available from: https://www. ncbi.nlm.nih.gov/books/NBK507848 [Last accessed on 2025 May 29].

 

  1. Sapolsky RM. Doubled-edged swords in the biology of conflict. Front Psychol. 2018;9:2625. doi: 10.3389/fpsyg.2018.02625

 

  1. Gimpl G, Fahrenholz F. The oxytocin receptor system: Structure, function, and regulation. Physiol Rev. 2001;81(2):629-683. doi: 10.1152/physrev.2001.81.2.629

 

  1. Petersson M, Alster P, Lundeberg T, Uvnäs-Moberg K. Oxytocin causes a long-term decrease of blood pressure in female and male rats. Physiol Behav. 1996;60(5):1311-1315. doi: 10.1016/s0031-9384(96)00261-2

 

  1. Petty MA, Lang RE, Unger T, Ganten D. The cardiovascular effects of oxytocin in conscious male rats. Eur J Pharmacol. 1985;112(2):203-210. doi: 10.1016/0014-2999(85)90497-2

 

  1. Verbalis JG, Dohanics J. Vasopressin and oxytocin secretion in chronically hyposmolar rats. Am J Physiol. 1991;261(4 Pt 2):R1028-R1038. doi: 10.1152/ajpregu.1991.261.4.R1028

 

  1. Schmidt A, Jard S, Dreifuss JJ, Tribollet E. Oxytocin receptors in rat kidney during development. Am J Physiol. 1990;259(6 Pt 2):F872-F881. doi: 10.1152/ajprenal.1990.259.6.F872

 

  1. Kennett JE, McKee DT. Oxytocin: An emerging regulator of prolactin secretion in the female rat. J Neuroendocrinol. 2012;24(3):403-412. doi: 10.1111/j.1365-2826.2011.02263.x

 

  1. Szewczyk AK, Ulutas S, Aktürk T, et al. Prolactin and oxytocin: Potential targets for migraine treatment. J Headache Pain. 2023;24(1):31. doi: 10.1186/s10194-023-01557-6

 

  1. Villar Taibo R, Sifontes Dubon M, Morón IB, Casanueva FF. Prolactin excess and deficiency: Epidemiology, causes (Excluding prolactin-secreting pituitary tumors). In: Tritos NA, Klibanski A, editors. Prolactin Disorders: From Basic Science to Clinical Management. Berlin: Springer International Publishing; 2019. p. 95-110. doi: 10.1007/978-3-030-11836-5_5

 

  1. Krause DN, Warfvinge K, Haanes KA, Edvinsson L. Hormonal influences in migraine - interactions of oestrogen, oxytocin and CGRP. Nat Rev Neurol. 2021;17(10):621-633. doi: 10.1038/s41582-021-00544-2

 

  1. Ikegami D, Navratilova E, Yue X, et al. A prolactin-dependent sexually dimorphic mechanism of migraine chronification. Cephalalgia. 2022;42(3):197-208. doi: 10.1177/03331024211039813

 

  1. Diogenes A, Patwardhan AM, Jeske NA, et al. Prolactin modulates trpv1 in female rat trigeminal sensory neurons. J Neurosci. 2006;26(31):8126-8136. doi: 10.1523/JNEUROSCI.0793-06.2006

 

  1. Avona A, Mason BN, Burgos‐Vega C, et al. Meningeal CGRP ‐prolactin interaction evokes female‐specific migraine behavior. Ann Neurol. 2021;89(6):1129-1144. doi: 10.1002/ana.26070

 

  1. Chen Y, Navratilova E, Dodick DW, Porreca F. An emerging role for prolactin in female-selective pain. Trends Neurosci. 2020;43(8):635-648. doi: 10.1016/j.tins.2020.06.003

 

  1. Chen Y, Moutal A, Navratilova E, et al. The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females. Sci Transl Med. 2020;12(529):eaay7550. doi: 10.1126/scitranslmed.aay7550

 

  1. Paige C, Barba-Escobedo PA, Mecklenburg J, et al. Neuroendocrine mechanisms governing sex differences in hyperalgesic priming involve prolactin receptor sensory neuron signaling. J Neurosci. 2020;40(37):7080-7090. doi: 10.1523/JNEUROSCI.1499-20.2020

 

  1. Patil M, Belugin S, Mecklenburg J, et al. Prolactin regulates pain responses via a female-selective nociceptor-specific mechanism. iScience. 2019;20:449-465. doi: 10.1016/j.isci.2019.09.039

 

  1. Patil M, Hovhannisyan AH, Wangzhou A, et al. Prolactin receptor expression in mouse dorsal root ganglia neuronal subtypes is sex-dependent. J Neuroendocrinol. 2019;31(8):e12759. doi: 10.1111/jne.12759

 

  1. Alia S, Ali RS, Nafiseh E, Ehsan K. Comparison the serum level of prolactin among patients with chronic and episodic migraine. J Neurol Res. 2013;3(2):68-72. doi: 10.4021/jnr.v3i2.189

 

  1. Masoud SA, Fakharian E. Serum prolactin and migraine. Ann Saudi Med. 2005;25(6):489-491. doi: 10.5144/0256-4947.2005.489

 

  1. Peres MFP. Hypothalamic involvement in chronic migraine. J Neurol Neurosurg Psychiatry. 2001;71(6):747-751. doi: 10.1136/jnnp.71.6.747

 

  1. Delaruelle Z, Ivanova TA, Khan S, et al. Male and female sex hormones in primary headaches. J Headache Pain. 2018;19(1):117. doi: 10.1186/s10194-018-0922-7

 

  1. MacGregor EA. Menstrual and perimenopausal migraine: A narrative review. Maturitas. 2020;142:24-30. doi: 10.1016/j.maturitas.2020.07.005

 

  1. Martin VT, Lipton RB. Epidemiology and biology of menstrual migraine. Headache. 2008;48 Suppl 3:S124-S13. doi: 10.1111/j.1526-4610.2008.01310.x

 

  1. Somerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology. 1972;22(4):355-365. doi: 10.1212/wnl.22.4.355

 

  1. MacGregor EA. Oestrogen and attacks of migraine with and without aura. Lancet Neurol. 2004;3(6):354-361. doi: 10.1016/S1474-4422(04)00768-9

 

  1. King TS, Steger RW, Morgan WW. Effect of ovarian steroids to stimulate region-specific hypothalamic 5-hydroxytryptamine synthesis in ovariectomized rats. Neuroendocrinology. 1986;42(4):344-350. doi: 10.1159/000124461

 

  1. Bharadwaj VN, Porreca F, Cowan RP, Kori S, Silberstein SD, Yeomans DC. A new hypothesis linking oxytocin to menstrual migraine. Headache. 2021;61(7):1051-1059. doi: 10.1111/head.14152

 

  1. Stock S, Bremme K, Uvnäs-Moberg K. Plasma levels of oxytocin during the menstrual cycle, pregnancy and following treatment with HMG. Hum Reprod. 1991;6(8):1056-1062. doi: 10.1093/oxfordjournals.humrep.a137484

 

  1. Engel S, Klusmann H, Ditzen B, Knaevelsrud C, Schumacher S. Menstrual cycle-related fluctuations in oxytocin concentrations: A systematic review and meta-analysis. Front Neuroendocrinol. 2019;52:144-155. doi: 10.1016/j.yfrne.2018.11.002

 

  1. Salonia A, Nappi RE, Pontillo M, et al. Menstrual cycle-related changes in plasma oxytocin are relevant to normal sexual function in healthy women. Horm Behav. 2005;47(2):164-169. doi: 10.1016/j.yhbeh.2004.10.002

 

  1. Draper CF, Duisters K, Weger B, et al. Menstrual cycle rhythmicity: Metabolic patterns in healthy women. Sci Rep. 2018;8(1):14568. doi: 10.1038/s41598-018-32647-0

 

  1. Richard S, Zingg HH. The human oxytocin gene promoter is regulated by estrogens. J Biol Chem. 1990;265(11):6098- 6103.

 

  1. Amico JA, Seif SM, Robinson AG. Oxytocin in human plasma: Correlation with neurophysin and stimulation with estrogen. J Clin Endocrinol Metab. 1981;52(5):988-993. doi: 10.1210/jcem-52-5-988

 

  1. Chiodera P, Volpi R, Capretti L, et al. Effect of estrogen or insulin-induced hypoglycemia on plasma oxytocin levels in bulimia and anorexia nervosa. Metabolism. 1991;40(11):1226-1230. doi: 10.1016/0026-0495(91)90220-q

 

  1. Chung SK, McCabe JT, Pfaff DW. Estrogen influences on oxytocin mRNA expression in preoptic and anterior hypothalamic regions studied by in situ hybridization. J Comp Neurol. 1991;307(2):281-295. doi: 10.1002/cne.903070209

 

  1. Shughrue PJ, Dellovade TL, Merchenthaler I. Estrogen modulates oxytocin gene expression in regions of the rat supraoptic and paraventricular nuclei that contain estrogen receptor-beta. Prog Brain Res. 2002;139:15-29. doi: 10.1016/s0079-6123(02)39004-6

 

  1. Tzabazis A, Mechanic J, Miller J, et al. Oxytocin receptor: Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders. Cephalalgia. 2016;36(10):943-950. doi: 10.1177/0333102415618615

 

  1. Goadsby PJ, Goldberg J, Silberstein SD. Migraine in pregnancy. BMJ. 2008;336(7659):1502-1504. doi: 10.1136/bmj.39559.675891.AD

 

  1. van Lohuizen R, Paungarttner J, Lampl C, MaassenVanDenBrink A, Al-Hassany L. Considerations for hormonal therapy in migraine patients: A critical review of current practice. Expert Rev Neurother. 2023;24(1):55-75. doi: 10.1080/14737175.2023.2296610

 

  1. Sances G, Granella F, Nappi RE, et al. Course of migraine during pregnancy and postpartum: A prospective study. Cephalalgia. 2003;23(3):197-205. doi: 10.1046/j.1468-2982.2003.00480.x

 

  1. Scharff L, Marcus DA, Turk DC. Headache during pregnancy and in the postpartum: A prospective study. Headache. 1997;37(4):203-210. doi: 10.1046/j.1526-4610.1997.3704203.x

 

  1. Hoshiyama E, Tatsumoto M, Iwanami H, et al. Postpartum migraines: A long-term prospective study. Intern Med. 2012;51(22):3119-3123. doi: 10.2169/internalmedicine.51.8542

 

  1. Edvinsson L, Warfvinge K. Recognizing the role of CGRP and CGRP receptors in migraine and its treatment. Cephalalgia. 2019;39(3):366-373. doi: 10.1177/0333102417736900

 

  1. Maddahi A, Edvinsson JCA, Edvinsson L. Sex differences in expression of CGRP family of receptors and ligands in the rat trigeminal system. J Headache Pain. 2024;25(1):193. doi: 10.1186/s10194-024-01893-1

 

  1. Iyengar S, Johnson KW, Ossipov MH, Aurora SK. CGRP and the trigeminal system in migraine. Headache. 2019;59(5):659-681. doi: 10.1111/head.13529

 

  1. Spekker E, Tanaka M, Szabó Á, Vécsei L. Neurogenic inflammation: The participant in migraine and recent advancements in translational research. Biomedicines. 2021;10(1):76. doi: 10.3390/biomedicines10010076

 

  1. Holzer P. Neurogenic vasodilatation and plasma leakage in the skin. Gen Pharmacol. 1998;30(1):5-11. doi: 10.1016/s0306-3623(97)00078-5

 

  1. Raddant AC, Russo AF. Calcitonin gene-related peptide in migraine: Intersection of peripheral inflammation and central modulation. Expert Rev Mol Med. 2011;13:e36. doi: 10.1017/S1462399411002067

 

  1. Maddahi A, Edvinsson L, Warfvinge K. Expression of vasopressin and its receptors in migraine-related regions in CNS and the trigeminal system: Influence of sex. J Headache Pain. 2022;23(1):152. doi: 10.1186/s10194-022-01524-7

 

  1. Warfvinge K, Krause D, Edvinsson L. The distribution of oxytocin and the oxytocin receptor in rat brain: Relation to regions active in migraine. J Headache Pain. 2020;21(1):10. doi: 10.1186/s10194-020-1079-8

 

  1. Warfvinge K, Krause DN, Maddahi A, et al. Oxytocin as a regulatory neuropeptide in the trigeminovascular system: Localization, expression and function of oxytocin and oxytocin receptors. Cephalalgia. 2020;40(12):1283-1295. doi: 10.1177/0333102420929027

 

  1. Nappi R, Tiranini L, Sacco S, De Matteis E, De Icco R, Tassorelli C. Role of estrogens in menstrual migraine. Cells. 2022;11(8):1355. doi: 10.3390/cells11081355

 

  1. Hewitt SC, Korach KS. Estrogen receptors: New directions in the new millennium. Endocr Rev. 2018;39(5):664-675. doi: 10.1210/er.2018-00087

 

  1. Borsook D, Erpelding N, Lebel A, et al. Sex and the migraine brain. Neurobiol Dis. 2014;68:200-214. doi: 10.1016/j.nbd.2014.03.008

 

  1. Shughrue PJ, Merchenthaler I. Estrogen is more than just a “sex hormone”: Novel sites for estrogen action in the hippocampus and cerebral cortex. Front Neuroendocrinol. 2000;21(1):95-101. doi: 10.1006/frne.1999.0190

 

  1. Sacco S, Ricci S, Degan D, Carolei A. Migraine in women: The role of hormones and their impact on vascular diseases. J Headache Pain. 2012;13(3):177-189. doi: 10.1007/s10194-012-0424-y

 

  1. Waliszewska-Prosół M, Grandi G, Ornello R, et al. Menopause, perimenopause, and migraine: Understanding the intersections and implications for treatment. Neurol Ther. 2025;14(3):665-680. doi: 10.1007/s40120-025-00720-2

 

  1. Spekker E, Bohár Z, Fejes-Szabó A, Szűcs M, Vécsei L, Párdutz Á. Estradiol treatment enhances behavioral and molecular changes induced by repetitive trigeminal activation in a rat model of migraine. Biomedicines. 2022;10(12):3175. doi: 10.3390/biomedicines10123175

 

  1. Avona A, Burgos-Vega C, Burton MD, Akopian AN, Price TJ, Dussor G. Dural calcitonin gene-related peptide produces female-specific responses in rodent migraine models. J Neurosci. 2019;39(22):4323-4331. doi: 10.1523/JNEUROSCI.0364-19.2019

 

  1. Noori-Zadeh A, Karamkhani M, Seidkhani-Nahal A, Khosravi A, Darabi S. Evidence for hyperprolactinemia in migraineurs: A systematic review and meta-analysis. Neurol Sci. 2020;41(1):91-99. doi: 10.1007/s10072-019-04035-7

 

  1. Gazerani P. A link between migraine and prolactin: The way forward. Future Sci OA. 2021;7(9):FSO748. doi: 10.2144/fsoa-2021-0047

 

  1. Cavestro C, Rosatello A, Marino MP, Micca G, Asteggiano G. High prolactin levels as a worsening factor for migraine. J Headache Pain. 2006;7(2):83-89. doi: 10.1007/s10194-006-0272-8

 

  1. Wang YL, Yuan Y, Yang J, et al. The interaction between the oxytocin and pain modulation in headache patients. Neuropeptides. 2013;47(2):93-97. doi: 10.1016/j.npep.2012.12.003

 

  1. You DS, Haney R, Albu S, Meagher MW. Generalized pain sensitization and endogenous oxytocin in individuals with symptoms of migraine: A cross‐sectional study. Headache. 2018;58(1):62-77. doi: 10.1111/head.13213

 

  1. Hartman N, Voron SC, Hershman JM. Resolution of migraine following bromocriptine treatment of a prolactinoma (Pituitary microadenoma). Headache. 1995;35(7):430-431. doi: 10.1111/j.1526-4610.1995.hed3507430.x

 

  1. Liu N, Yang H, Han L, Ma M. Oxytocin in women’s health and disease. Front Endocrinol (Lausanne). 2022;13:786271. doi: 10.3389/fendo.2022.786271

 

  1. Phillips WJ, Ostrovsky O, Galli RL, Dickey S. Relief of acute migraine headache with intravenous oxytocin: Report of two cases. J Pain Palliat Care Pharmacother. 2006;20(3):25-28.
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