Sex Hormones May Play an Important Role in Multiple Sclerosis Prevalence and Development

In a review of sex hormones and their role in the development of multiple sclerosis (MS), Ysrraelit and Correale compiled multiple references to provide clinical details regarding hormones and their respective immunological mechanisms.

MS is a chronic, autoimmune, inflammatory disease occurring in a female/male ratio of 3:1. While women are more likely to get MS and suffer more frequent relapses, men progress to disability faster and have poorer recovery after the first disease relapse. Research regarding sex hormones have extensively been analyzed due to the pre-existing knowledge that hormone receptors affect immune cells. An understanding of the role of sex hormones in MS can lead to new pathways for therapies.

The 4 main sex hormones that have been shown to affect the immune system are estrogen, progesterone, androgen, and prolactin. Estrogen produced endogenously include estrone (E1), 17-β estradiol (E2) and estriol (E3, produced only in pregnancy). E2 has been shown to have an anti-inflammatory effect by inhibiting the production of proinhibitory cytokines (IL-1, IL-6, TNF-α), natural killer (NK) cells activation, and induce the expression of anti-inflammatory cytokines (IL-4, IL-10). However, at low concentrations (preovulatory), E2 exerts the opposite effect and instead is proinflammatory. This was seen in patients who went through ovariectomy and reported earlier autoimmune encephalomyelitis (EAE). Treatment of EAE through high levels of E2 with E3 postponed the disease, indicating an anti-inflammatory effect through estrogen use. In 1 clinical trial, E3 use in women with relapsing/remitting MS (RRMS) caused decreases in IFN-γ and smaller gadolinium-enhancing lesions. In another trial, E3 combined with glatiramer acetate in women with RRMS also lowered relapse rates; however, no differences were observed for gadolinium-enhancing lesions, T2 lesions, or total brain volume.

Progesterone is another sex hormone that has receptors on immune cells. Progesterone normally creates anti-inflammatory responses and causes T-reg cell differentiation, the downregulation of IFN-γ and NK cells, and an increased proliferation of oligodendrocyte progenitor cells, promoting myelin protein synthesis. Yet, when progesterone was administered to patients to prevent MS relapses postpartum, there was no protective effect.

Androgens, such as testosterone, are also an area of interest and are believed to give protection against autoimmunity due to the lower autoimmune disease incidence in men. The later age of onset in men may correlate to the age-related decline in testosterone, and lower levels of testosterone correlated with increased disease severity and poorer cognitive function. In 1 study, male patients with MS treated with testosterone gel showed a significant slowing of brain atrophy and improvements in cognitive testing, showing a potential neuroprotective effect. However, testosterone did not influence gadolinium-enhancing lesions.

The effect of prolactin on MS is disputed as some studies found an increased level in MS patients during release, while other studies did not find a link to disease activity. In addition, prolactin administered at a low dose did not affect MS, but a high dose did. Bromocriptine, a prolactin suppressor, was able to inhibit lymphocyte proliferation, suggesting that prolactin may be a detrimental factor in MS. However, prolactin also causes proliferation of oligodendrocyte precursor cells and promotes myelin repair. Prolactin seems to exert a dual effect in MS and is not recommended as a therapeutic agent.

Because of the effect that sex hormones exert on the immune system, it is very probable that these hormones also influence the prevalence and the course of MS. As more information is obtained, different therapies affecting the regulation of these hormones may lead to alternative treatments for patients with MS.

Reference

Ysrraelit MC, Correale J. Impact of sex hormones on immune function and MS development [published online September 17, 2018]. Immunology. doi: 10.1111/imm.13004.