A Link Between Migraine and Prolactin: the Way Forward

Abstract

Migraine is an incapacitating neurological disorder that predominantly affects women. Sex and other hormones (e.g., oxytocin, and prolactin) may play a role in sexual dimorphic features of migraine. Initially, prolactin was recognized for its modulatory action in milk production and secretion; later, its roles in the regulation of the endocrine, immune and nervous systems were discovered. Higher prolactin levels in individuals with migraine were found in earlier studies, with a female sex-dominant trend. Studies that are more recent have identified that the expression of prolactin receptor in response to neuronal excitability and stress depends on sex with a dominant role in females. These findings have opened up potentials for explanation of sex-related pathophysiology of migraine, but have left some unanswered questions. This focused review examines the past and present of the link between prolactin and migraine, and presents open questions and directions for future experimental and clinical efforts.

Association between dietary folate intake and severe headache among adults in the USA: a cross-sectional survey

“…Severe headache or migraines are highly prevalent in adults under the age of 50 years and women, on average, are at roughly three times the risk of developing migraine than man (32) . In stratified analysis by gender and age, dietary folate consumption was only associated with severe headache in women aged 20-50 years old.…”

Kappa opioid receptor agonists produce sexually dimorphic and prolactin-dependent hyperalgesic priming

“…Prolactin has recently been suggested to be a factor in promoting increased pain in functional pain syndromes including migraine. 3,19,27,30,51,72,80 The frequency of migraine is greater in both male and female patients with PRL-secreting tumors who exhibit extremely high levels of circulating PRL, and these patients often show improvement after treatment with dopamine D2 receptor agonists including cabergoline or bromocriptine. 11,36,71,81,82 We therefore reasoned that exogenous KOR agonists would mimic the effects of repeated stress by disinhibiting dopaminergic control of circulating PRL to promote nociceptor sensitization in females.…”

Molecular mechanisms of hormones implicated in migraine and the translational implication for transgender patients

“…Prolactin is predominantly synthesized from lactotroph cells expressing G-protein-coupled dopamine D2 receptors in the anterior pituitary but can also be produced from the gonads, endothelial cells, and adipose tissue to regulate endocrine, immune, and nervous system activity ( 76 , 77 ). Serum prolactin levels are regulated by a short feedback loop in which synthesis of the neurotransmitter dopamine within tuberoinfundibular dopamine (TIDA) neurons in the arcuate nucleus (ARC) is promoted by high prolactin levels to inhibit prolactin signaling ( 76 ).…”

“…PRL-L activates signaling pathways involved in long-term potentiation—such as the Src family of tyrosine kinases, phosphatidylinositol 3-kinase (PI3K)/protein kinase B, MAPK, and serine/threonine kinase Nek3-Vav2-Rac1 pathways—which implies that prolactin could reinforce central sensitization and neurogenic inflammation. However, animal studies suggest that trigeminal hyperexcitability is incited through PRL-S activation and TRP channel sensitization—specifically, potentiation of TRPV1 in the trigeminal ganglion and the TRP subfamilies V1, A1, and M8 in dorsal root ganglia from PI3K and protein kinase C δ downstream signaling—which generates central sensitization that is more prominent in female murine models ( 77 ).…”