Estrogen and testosterone therapies in multiple sclerosis
Introduction
Multiple sclerosis (MS) is a heterogeneous inflammatory, demyelinating, and degenerative disease of a presumed Th1-autoimmune origin that occurs in genetically susceptible individuals (Hemmer et al., 2002). The exact pathogenetic mechanisms are unknown, but peripheral activation of autoreactive CD4+ T cells targeting proteins of the myelin sheath of neurons has been hypothesized as a key process in the development of the disease (McFarland and Martin, 2007). Upon activation, these cells cross the blood-brain barrier to enter the central nervous system (CNS), recognize myelin antigens, and initiate a chronic inflammatory cascade that results in demyelination of axons, mainly by macrophages (Sospedra and Martin, 2005). Involvement of humoral (antibodies and complement) and cellular mechanisms, as well as primary oligodendroglial degeneration and apoptosis, has also been proposed (Lassmann et al., 2001). The pathological hallmark is the demyelinated plaque, which consists of well-demarcated areas characterized by the loss of myelin and formation of astrocytic scars. However, it is becoming increasingly clear that axonal loss may be the major determinant for long-term, permanent disability. It is unclear whether all neurodegeneration is directly related to acute inflammation, since diffuse axonal damage may occur separately from pathological lesions (Evangelou et al., 2000), and even robust and effective immunosuppression with chemotherapeutic agents is not sufficient to stop accumulation of disability, in particular during later disease stages (Coles et al., 2006). Thus, it appears that MS has both an inflammatory and a neurodegenerative component in its pathogenesis. Over the last decade, abundant neuroimaging and neuropathological studies have indicated a significant neurodegenerative process in MS. Neuroimaging has demonstrated atrophy (Brex et al., 2000; Filippi et al., 2003; Ge et al., 2000; Losseff et al., 1996; Rudick et al., 1999; Stevenson et al., 1998), particularly in gray matter (Bakshi et al., 2001; Catalaa et al., 1999; Rudick et al., 1999). This gray matter atrophy has been shown to correlate better with permanent disability than does the white matter inflammatory marker of gadolinium-enhancing lesions (Ge et al., 2000; Rudick et al., 1999; Stevenson et al., 1998). Also, abnormalities beyond classic white matter T2 hyperintensities, within “normal-appearing white matter” (NAWM), have been shown using magnetization transfer, spectroscopy, and diffusion-weighted imaging (Catalaa et al., 2000; De Stefano et al., 1999; Filippi et al. (2000a), Filippi et al. (2000b); Gasperini et al., 1996; Narayanan et al., 1997; Santos et al., 2002; Tortorella et al., 2000). Furthermore, the degree of change in the NAWM may be a predictor of future clinical progression (Santos et al., 2002). Pathological findings in MS have described cortical lesions that were characterized by transected neurites (both axons and dendrites) and apoptosis with very little T and B cell infiltration (Bo et al., 2003; Peterson et al., 2001). Axonal transection has also been described within white matter lesions, raising the possibility of Wallerian degeneration in white matter tracts.
In light of these observations, there is now a consensus by MS investigators that there is a need to discover novel treatment options that combine neuroprotective properties with anti-inflammatory effects. In this paper, we will outline the scientific basis for sex hormones as putative treatment options in MS as well as other CNS diseases with both an inflammatory and a neurodegenerative component and review potential mechanisms of action.
The concept that sex hormones may play a role in MS pathogenesis and disease activity and could, therefore, potentially be used for therapeutic interventions is based on two well-established clinical observations: a higher prevalence of MS in females compared to males and a decrease in disease activity during pregnancy, in particular in the third trimester. In the following text, we will briefly outline the evidence for these two phenomena and their relevance for sex hormone treatments in MS. For a comprehensive overview of this area, we refer the reader to a recent review published elsewhere (Voskuhl, 2009).
Many autoimmune diseases are more prevalent in women than in men. In MS, there is a female-to-male preponderance approaching 2:1 to 3:1 (Duquette et al., 1992), and recent evidence seems to suggest that the gender gap is widening (Orton et al., 2006). The causes for the gender bias in MS and other autoimmune diseases may include sex-linked genetic factors, sex differences in immune responsiveness, and/or sex steroid effects (Whitacre et al., 1999). Interestingly, a later onset of disease in male patients compared to female patients (Weinshenker, 1994) coincides with a decline in bioavailable testosterone in men (Swerdloff and Wang, 2004). Although only a minority of male patients with MS have demonstrated testosterone levels significantly below the normal range (Foster et al., 2003; Wei and Lightman, 1997), these findings suggest that testosterone may be protective in young men genetically susceptible to MS. There is an ongoing controversy whether established MS progresses at different speeds in men and women. A detailed review of the empirical evidence in this area can be found elsewhere (Voskuhl, 2009). Taken together, the data suggest that men are less likely to develop clinical relapses and enhancing lesions on magnetic resonance imaging (MRI), but it remains unclear if there is a gender difference regarding progression of clinical disease or neurodegeneration on MRI. Generally, this is in line with a beneficial, anti-inflammatory effect of endogenous testosterone in MS.
It has been appreciated for decades that symptoms of patients with autoimmune diseases are affected by pregnancy and the postpartum period. MS patients as well as individuals with other inflammatory autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis experience clinical improvement during pregnancy, with a temporary “rebound” exacerbation postpartum (Abramsky, 1994; Birk et al., 1990; Confavreux et al., 1998; Da Silva and Spector, 1992; Damek and Shuster, 1997; Nelson et al., 1992; Runmarker and Andersen, 1995). The most definitive study of the effect of pregnancy on MS came in 1998 by the Pregnancy in Multiple Sclerosis (PRIMS) Group (Confavreux et al., 1998). This study followed 254 women with MS for up to 1 year postdelivery and showed that relapse rates were significantly reduced from 0.7 per woman per year in the year before pregnancy to 0.2 during the third trimester. Rates then increased to 1.2 during the first 3 months postpartum before returning to pre-pregnancy rates. Together these data clearly demonstrated that late pregnancy is associated with a significant reduction in relapses, while there is a rebound increase in relapses postpartum. It is, however, unclear if this effect on relapse rate translates into a beneficial effect on long-term disability. One short-term 2-year follow-up study indicated that there is no “net” effect of a single pregnancy on disability (Vukusic et al., 2004). However, a long-term study in 200 women showed that patients who had at least one pregnancy after onset were wheelchair dependent after 18.6 years, versus 12.5 years for the other women (Verdru et al., 1994), indicating a protective effect of pregnancy on long-term disability accumulation. Thus, there is clear evidence that pregnancy has a potent short-term effect on inflammation and relapse rate, but data regarding long-term effects on disability are inconclusive.
Pregnancy is characterized by an array of biological changes that could mediate both immunomodulatory and neuroprotective effects. First, a pronounced systemic shift from Th1-type cellular immunity toward Th2-type humoral immunity can be observed during pregnancy (Whitacre et al., 1999). This immune shift, rather than a general immune suppression, is beneficial during pregnancy for two reasons: The fetus represents an “allograft” in immunological terms, since it harbors antigens inherited from the father, and the natural immunomodulation is thus important to prevent fetal rejection. However, the developing fetus depends on the mother for the passive transport of antibodies in light of its immature immune system, and this antibody production is supported by a shift toward Th2-type humoral immunity. Second, pregnancy is characterized by the presence of potentially neuroprotective hormones, including estrogens, progesterone, and prolactin. The secretion of these factors are thought to play a crucial role for the CNS neuronal and oligodendroglial cell lineages during development (Craig et al., 2003).
From an evolutionary standpoint, biological changes during pregnancy are generally aimed at protecting the fetus and promoting its development. However, the same mechanisms, that is, suppression of cellular immunity and promotion of neuroprotection, may coincidentally also be highly beneficial for a mother with an autoimmune inflammatory CNS disease. One could therefore consider the advantageous effects in MS a side effect of pregnancy. Importantly, this “side effect” can provide valuable insight into MS pathology as well as highlight new therapeutic avenues.
Numerous factors that have been identified in blood during pregnancy have been shown to be immunomodulatory, including estrogens, cortisol, progesterone, vitamin D, early pregnancy factor (EPF), α-fetoprotein, and others, some of which also have neuroprotective properties. Estriol is one of the major candidates as a therapeutic agent in MS since it has potent effects on both the immune system as well as the CNS and peaks during the last trimester, that is, when the most pronounced decrease in relapse rate occurs.
Section snippets
Testosterone
The protective role of testosterone in autoimmunity in vivo has been demonstrated by the deleterious effect of castration of male animals on disease susceptibility and severity in numerous models of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), diabetes in nonobese mice, thyroiditis, and adjuvant arthritis (Ahmed and Penhale, 1982; Bebo et al., 1998; Fitzpatrick et al., 1991; Fox, 1992; Harbuz et al., 1995; Smith et al., 1999). Conversely, testosterone
Testosterone
In a pilot clinical trial, 10 male MS patients were treated with 10 g of gel containing 100 mg of testosterone in a crossover design (6-month observation period followed by 12 months of treatment) (Sicotte et al., 2007). Clinical measures of disability and cognition (the Multiple Sclerosis Functional Composite and the 7/24 Spatial Recall Test) were obtained every 3 months. In addition, monthly MRI measures of enhancing lesion activity and whole brain volumes were acquired. In addition, blood was
Conclusions and future directions
A large body of evidence supports the therapeutic potential of testosterone and estrogens in animal models of MS. Mechanisms of action include both immunomodulatory and neuroprotective pathways, thus suggesting that sex hormones represent novel treatment options that could beneficially affect the inflammatory as well as the neurodegenerative component of the disease. We now also have first clinical evidence for the effectiveness of testosterone and estriol in MS from two completed pilot
Abbreviations
- BDNF
brain-derived neurotrophic factor
- CNS
central nervous system
- DHT
dehydrotestosterone
- DTH
delayed-type hypersensitivity
- EAE
experimental autoimmune encephalomyelitis
- ER
estrogen receptor
- IL
interleukin
- IFN
interferon
- MMP
matrix metalloproteinase
- MRI
magnetic resonance imaging
- MS
multiple sclerosis
- NAWM
normal-appearing white matter
- PASAT
paced auditory serial-addition task
- PBMC
peripheral blood mononuclear cell
- PDGF
platelet-derived growth factor
- RA
rheumatoid arthritis
- RRMS
relapsing-remitting MS
- SPMS
secondary-progressive
Acknowledgments
The authors would like to thank Donna Crandall for producing the artwork for Fig. 1. We would also like to thank all members of the UCLA MS program for their conceptual contributions to the model in Fig. 1.
References (113)
- et al.
Gonadal hormones influence the immune response to PLP 139-151 and the clinical course of relapsing experimental autoimmune encephalomyelitis
Journal of Neuroimmunology
(1998) - et al.
17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro
Biochemical and Biophysical Research Communications
(1995) - et al.
Quantitative analysis of perinatal rodent oligodendrocyte lineage progression and its correlation with human
Experimental Neurology
(2003) - et al.
Pregnancy and multiple sclerosis
Mayo Clinic Proceedings
(1997) - et al.
Dysregulation of the hypothalamic-pituitary-gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis
Journal of Neuroimmunology
(2003) - et al.
Neuroprotection by estradiol
Progress in Neurobiology
(2001) - et al.
Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice
Journal of Neuroimmunology
(1994) - et al.
Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy
Trends in Molecular Medicine
(2001) Sex hormone modulation of neural development in vitro
Hormones and Behavior
(1994)- et al.
Steroid hormones protect spinal cord neurons from glutamate toxicity
Neuroscience
(1993)