Hypothalamic and sex-related hormones in migraine.

The hypothalamus and sex hormones are closely linked to primary headache disorders. Migraine is the most prevalent disabling neurological disorder, affecting up to 15% of the global population, with enormous socioeconomic and personal impacts. It ranks second among years lived with disability (YLD), with women being the most affected, experiencing a threefold higher prevalence than men. Women report more severe migraine symptoms during periods of sex hormone fluctuations, particularly at puberty, during pregnancy, and around perimenopause. The reason for this sex-based difference remains unclear. However, it is apparent that dynamic fluctuations in female sex hormone levels (oestrogen, progesterone) have a key influence on the susceptibility to attacks in women. A fall in plasma levels of oestrogen, progesterone, and hypothalamic oxytocin may trigger migraine attacks, whereas higher levels appear to be protective. Circulating hormones show dynamic alterations, and, more importantly, their receptors are expressed in the trigeminovascular system (TGVS). Notably, other hormones, such as testosterone and vasopressin (AVP), are less extensively studied but are also highlighted in this review. The underlying mechanisms of their effects on migraine targets have yet to be explained. This review highlights the interplay between sex/reproductive hormones and hypothalamic hormones and their receptors in migraine-related neural structures, both in the central nervous system and in the TGVS. We have included the hypothalamic hormones oxytocin and the molecularly related AVP due to the significant drop in oxytocin levels at the onset of menstruation, as well as its role in parturition and lactation. Recent data have revealed expression of oxytocin receptors in the TGVS. Oestrogen, acting through multiple receptor subtypes, influences expression levels of oxytocin and its receptor. Recent data have demonstrated a close transcriptional relationship between oestrogen and calcitonin gene-related peptide (CGRP), as well as the receptor component “receptor activity-modifying protein 1” (RAMP1), in migraine pathology and current successful treatments.