The role of androgens in migraine pathophysiology

Abstract

Migraine affects ∼12 % of the worldwide population and is more prevalent in females, which suggests a role of sex hormones in migraine pathophysiology. Most studies have focused on estrogen and progesterone, and the involvement of androgens has been less studied. However, due to the recent advances in androgen interventions, which could advance new androgen-based migraine treatments, it is critical to better understand the role of androgens in migraine. Testosterone, the most studied androgen, was found to have an antinociceptive effect in various animal and human pain studies. Thus, it could also have a protective effect related to lower migraine severity and prevalence. In this review, we discuss studies examining the role of androgens on migraine-related symptoms in migraine animal models. Additionally, we summarize the results of human studies comparing androgen levels between patients with migraine and healthy controls, studies assessing the relationships between androgen levels and migraine severity, and intervention studies examining the impact of testosterone treatment on migraine severity. Many of the studies have limitations, however, the results suggest that androgens may have a minor effect on migraine. Still, it is possible that androgens are involved in migraine pathophysiology in a sub-group of patients such as in adolescents or postmenopausal women. We discuss potential mechanisms in which testosterone, as the main androgen tested, can impact migraine. These mechanisms range from the cellular level to systems and behavior and include the effect of testosterone on sensory neurons, the immune and vascular systems, the stress response, brain function, and mood. Lastly, we suggest future directions to advance this line of research.

Keywords: Androgens; DHEA; Migraine; Pain; Sex hormones; Testosterone.

Fig. 1

Androgen synthesis. Androgen synthesis involves the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus which stimulates the secretion of luteinizing hormone (LH) and follicular-stimulating hormone (FSH) from the anterior pituitary (Sharma et al., 2022). In females, LH stimulates theca cells in the ovaries, producing a small amount of testosterone. In males, LH binds to specific receptors on Leydig cells in the testes to produce testosterone by regulating the conversion of cholesterol to pregnenolone. Pregnenolone is converted to dehydroepiandrosterone (DHEA), which is converted to androstenediol and androstenedione. The enzyme testosterone 17-beta-dehydrogenase converts these two hormones to testosterone(Miller and Auchus, 2019, Naamneh Elzenaty et al., 2022). Testosterone can be transferred in the blood by binding to circulating plasma protein and activate androgen receptors or it can be converted to either dihydrotestosterone (DHT) via the enzyme 5-alpha reductase or estradiol via aromatase(Handelsman 2020, Naamneh Elzenaty et al., 2022). Testosterone and the other steroids have a negative feedback loop by inhibiting the release of GnRH, LH, and FSH from the hypothalamus and pituitary gland (Plant and Marshall, 2001, Naamneh Elzenaty et al., 2022).

Fig. 2

Potential mechanisms involving the effect of testosterone on migraine. Testosterone may impact migraine via its effect on several factors. Diagramed is the effect of testosterone on the peripheral nervous, immune and vascular systems, the stress response, neural functions and mood, all of which can impact migraine. These factors can also interact with each other and further affect migraine.

Fig. 3

Potential androgen signaling mechanisms contributing to the sensory component of migraine. Migraine is a multimodal disease that can be explained, in part, by sensory neuron innervation of the meninges from the trigeminal ganglia. In this space there are neuroimmune interactions, which testosterone has the ability to modulate by potentially decreasing neuronal release of CGRP and inflammation. Multiple sensory neuron subtypes express androgen receptors (AR) including nociceptors and cells containing neuropeptides important for migraine pathophysiology. Together, it may be that a reduction in testosterone contributes to migraine.