2.3. Testosterone
A popular belief is that testosterone is the male hormone whereas estrogen is the female hormone. However, this is an oversimplification, as both estrogen and testosterone have important roles to play in individuals of either sex
[33][58]. In both males and females, the balance between estrogen and testosterone production throughout life influences the function of both reproductive and nonreproductive organs
[33][58].
Testosterone could be a potential therapeutic target, as it has an antinociceptive effect
[37][35][38][39][40][59,60,61,62,63]. In animal studies, after gonadectomy or the blocking of testosterone receptors, animals appeared more sensitive to nociceptive stimuli
[41][42][43][44][45][64,65,66,67,68]. The few human studies performed support an analgesic effect of testosterone, as higher testosterone levels are associated with lower experimental pain sensitivity
[46][69]. Studies on the relationship of testosterone to migraine are few. Testosterone levels are lower in adults with migraine vs. without migraine, and are related to migraine severity. Interestingly, even when similar testosterone levels are found, men with migraine more frequently report symptoms of androgen deficiency compared to men with no migraine. However, one study found that no differences in testosterone levels were found in women with vs. without migraine, and that migraine pain intensity was not correlated with testosterone levels.
Testosterone appears to be able to effectively reduce symptoms by suppressing spreading depressions, increasing serotonin, stabilizing cerebral blood flow, and reducing cell excitability and neuroinflammation [47][72]. These metabolic effects may explain the findings that testosterone treatment can improve clinical pain and experimental pain sensitivity in patients with chronic pain, including in patients with temporomandibular joint pain, fibromyalgia, and migraine [48][49][50][51][73,74,75,76], and that testosterone treatment delivered by a subcutaneous implant significantly reduces migraine intensity [50][75].
2.4. Oxytocin
Oxytocin’s (OT) therapeutic effects in migraine are complex and widespread in the nervous system, including at the level of the primary sensory neuron, spinal cord, and in a variety of brain regions associated with pain processing and modulation
[52][53][54][77,78,79].
The effect of OT on migraine has been shown via a case report in which intravenous OT provided analgesia and migraine relief
[55][80]. In addition, double-blind, placebo-controlled clinical studies have shown evidence that intranasal OT sprays are efficacious for treating migraine pain in adult men and women
[52][47][77,81] and experimental-evoked pain in men
[56][82]. A benefit of oxytocin as a treatment for migraine is that it is routinely administered intranasally for inducing labor, postpartum care, and for enhancing lactation, and its safety profile is well documented. In addition, intranasal oxytocin in humans has no major side effects
[49][83].
OT is a neuropeptide that exerts its pain-inhibitory effects both at the level of the primary afferent fiber and in the central nervous system. The first mechanism is via the descending neural pathway from the paraventricular nucleus (PVN) to the dorsal horn of the spinal cord
[50][51][84,85]. Signals from the PVN release oxytocin in the spinal dorsal horn that activate GABAergic interneurons in the dorsal horn which secondarily recruit other inhibitory GABAergic interneurons and suppress pain signals carried by ascending A-delta and C-fibers
[57][58][59][60][86,87,88,89]. The second mechanism is where OT released from the supraoptic nucleus (SON) in the hypothalamus, periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and the spinal dorsal horn
[61][62][90,91] modulates central endogenous pain pathways by raising nociceptive thresholds
[63][64][92,93].
OTR mRNA and proteins are expressed in nociceptive C-fibers and Aδ-fibers in the adult rat trigeminal ganglia [65][94], and have a high level of co-expression with CGRP in trigeminal ganglia neurons [57][77]. OT dose-dependently blocks the release of calcitonin gene-related peptide (CGRP) from trigeminal afferent neurons innervating the dura in vitro [65][94].
2.5. Vasopressin
Arginine vasopressin (AVP) is a neuropeptide hormone that has an antidiuretic effect in low concentrations, but at higher concentrations it causes vasoconstriction. Together, these effects raise blood pressure. AVP also has a role in pain, behavior, platelet aggregation, and blood coagulation functions.
Much of AVP is synthesized in the SON of the hypothalamus and, while AVP is largely stored in and secreted from the pituitary, AVP-containing hypothalamic fibers are widely distributed in the CNS [66][105]. These fibers reach different centers in the brainstem and, in particular, the trigemminal nuclei. The AVP receptors (VP1 and VP2) are found in the trigeminal ganglion [67].
[94]
2.6. Prolactin
Prolactin (PRL) is a hormone that is responsible for lactation, breast development, and hundreds of other actions needed to maintain homeostasis. PRL is chemically related to growth hormones and placental lactogen hormones. In an animal model, high levels of prolactin increased meningeal trigeminal pain sensitivity by only affecting CGRP in female rodents
[68][107].