Riley Bove1*
Annette Okai2Maria Houtchens3
Birte Elias-Hamp4
Alessandra Lugaresi5,6Kerstin Hellwig7
Eva Kubala Havrdová8- 1Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
- 2Multiple Sclerosis Treatment Center of Dallas, Dallas, TX, United States
- 3Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Boston, MA, United States
- 4Neurological Private Practice, Institute of Neuroimmunology and Multiple Sclerosis, Hamburg, Germany
- 5IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
- 6Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
- 7Department of Neurology, Ruhr University Bochum and St. Josef-Hospital, Bochum, Germany
- 8Department of Neurology and Center of Clinical Neuroscience, First Medical Faculty, General University Hospital, Charles University, Prague, Czechia
Over two thirds of all individuals who develop multiple sclerosis (MS) will be women prior to the age of menopause. Further, an estimated 30% of the current MS population consists of peri- or postmenopausal women. The presence of MS does not appear to influence age of menopausal onset. In clinical practice, symptoms of MS and menopause can frequently overlap, including disturbances in cognition, mood, sleep, and bladder function, which can create challenges in ascertaining the likely cause of symptoms to be treated. A holistic and comprehensive approach to address these common physical and psychological changes is often suggested to patients during menopause. Although some studies have suggested that women with MS experience reduced relapse rates and increased disability progression post menopause, the data are not consistent enough for firm conclusions to be drawn. Mechanisms through which postmenopausal women with MS may experience disability progression include neuroinflammation and neurodegeneration from age-associated phenomena such as immunosenescence and inflammaging. Additional effects are likely to result from reduced levels of estrogen, which affects MS disease course. Following early retrospective studies of women with MS receiving steroid hormones, more recent interventional trials of exogenous hormone use, albeit as oral contraceptive, have provided some indications of potential benefit on MS outcomes. This review summarizes current research on the effects of menopause in women with MS, including the psychological impact and symptoms of menopause on disease worsening, and the treatment options. Finally, we highlight the need for more inclusion of MS patients from underrepresented racial and geographic groups in clinical trials, including among menopausal women.
Introduction
Multiple sclerosis (MS) is a chronic, immune-mediated, inflammatory, demyelinating disease of the central nervous system (1), with a female-to-male incidence rate ratio of 3:1 (2). Since MS is typically diagnosed in young adulthood (3), a majority of women living with MS will undergo menopause after MS diagnosis. However, rates of late-onset MS have also increased, particularly among women (4). Further, since the advent of disease-modifying therapies (DMTs) to treat MS, the life expectancy and median age of patients living with MS has increased (3), thereby necessitating awareness among clinicians of the changing needs associated with older patients.
For both women and men, increasing age is associated with changes in the MS course, notably a switch from a predominantly relapsing-remitting course to progressive phenotypes with greater disability accumulation (5). The symptoms of MS in older patients may be further impacted not only from the effects of somatic aging but also from the effects of other neurodegenerative diseases that are typical in older age (3). In addition, the onset of menopause in women presents further challenges for the management of MS since some symptoms experienced during this life transition, such as cognitive impairment, depression and anxiety, sleep disturbance and fatigue, and bladder impairment, can overlap with those of MS (6).
Changes in the levels of sex steroid hormones in women over time have long been postulated to affect the MS course, for example based on the well-established observation of reduced relapse rates in the third trimester of pregnancy, followed by a rebound postpartum (7). Some preclinical data suggest that exogenous hormones could impact disease course/severity via effects on neuroprotection and inflammation (8–10). Although much of the existing evidence on whether estrogen could aid in alleviating the effects of MS is from studies of women receiving oral contraceptives (11–13), an early retrospective study suggested a beneficial effect of hormone therapy (HT) in menopause (14).
In this review, we summarize the evidence on whether menopause has effects on MS symptoms and disease outcomes, additional to those effects anticipated with advancing age, and whether intervention with HT could improve quality of life and impact the MS disease course in postmenopausal women. We then provide recommendations for general management of these patients and for future study.
Biology of Menopause and Functioning in MS
Menopause entails a number of physiological changes that affect women with MS through at least three physiological mechanisms: reproductive, immunological, and neurological. The onset of natural menopause in the general population typically occurs in the sixth decade of life; typically progesterone levels begin to decrease during the 30 s, whereas estrogen levels decline after a peak around the late 40 s (15). Anti-Müllerian hormone (AMH) is a key biomarker of ovarian aging, reflecting ovarian follicular reserve; levels generally peak around 25 years of age and gradually taper to undetectable by the time of menopause (16, 17).
The median age of natural menopause observed in women with MS is around 51 years (18, 19), aligning with that in the general population (20). Since AMH levels can give a more precise measure of ovarian reserve, they have also been investigated in case-control studies of women with MS. A study of women of reproductive age (N = 134) reported lower mean AMH levels in patients with MS (2.47 ± 0.26 ng/ml) compared with healthy controls (3.34 ± 0.34 ng/ml; p < 0.04) (21); in contrast, a larger study (N = 592) with a broader age range (22–65 years) found no difference in AMH levels by MS status (0.98-fold difference [95% CI, 0.69–1.37]; p = 0.87) (22). Therefore, it is not clear whether, overall, ovarian function is influenced by MS status.
Although several studies have evaluated the effect of menopause on aspects of MS disease course, including relapse rates, disability progression, and patient-reported outcomes, data are inconclusive. Over 10 years in a longitudinal study assessing disability progression in women with MS (N = 124), mean Expanded Disability Status Scale (EDSS) score increased from before to after menopause by 0.08 points (p = 0.02) (19). This finding was supported by a study of 148 women with MS that reported a greater mean EDSS score increase at an average of 3.5 years after menopause (0.4-point increase) compared with 3.5 years before menopause (0.2-point increase; p < 0.001); in contrast, annualized relapse rate (ARR) decreased from before to after menopause (0.21 vs. 0.13; p = 0.005) (23). Additionally, in an online reproductive history survey of 513 patients with MS, women who underwent surgical menopause had greater patient-reported disease severity as assessed by the MS Rating Scale (mean [SD] score: 13.1 [5.4]) compared with premenopausal women (mean [SD] score: 8.9 [5.5]; p < 0.0001 between groups); mean (SD) score for natural menopause was 9.6 (5.1) (18). A smaller retrospective study of 37 women with a diagnosis of MS prior to menopause supported declining relapse rate within 5 years after menopause (ARR: 0.08 vs. 0.37 before menopause; p < 0.001), but not increased disability, with no change reported after menopause for either EDSS progression rate (0.13-point increase per year both before and after menopause; p = 0.94) or frequency of EDSS progression events (37.8 vs. 48.6%; p = 0.42) (24). In a recent systematic review, when the data from the Baroncini et al. (23) and Ladeira et al. (24) studies were assessed in aggregate, no overall difference between relapse rates before and after menopause was found (risk ratio: 1.21; 95% CI, 0.91–1.61; p = 0.218) (25).
An important factor likely to contribute to age-related MS disability progression is immunosenescence, which affects both the adaptive and innate arms of the immune system (5, 26). Studies of peripheral biomarkers of immunosenescence have indicated that patients with MS may display a particular type of immunosenescence that can have a premature onset (27). Furthermore, menopause-related declines in sex hormone levels may contribute to a reproductive senescence (28) that would add to the effects of more general age-related immunosenescence (29, 30). For example, some data suggest declining ovarian reserve is associated with neurodegeneration in MS patients, as evidenced by brain volume loss. In a cohort study of 412 women with MS, 10-fold lower AMH levels were linked with accelerated reduction of gray matter volume in both a cross-sectional analysis (change in cortical gray matter: −7.44 mm3; p = 0.041) and a longitudinal analysis with up to 10 years of follow-up (change in cortical gray matter: −4.55 mm3; p = 0.062) and increased EDSS score (cross-sectional analysis: 0.43-point increase [p = 0.003]; longitudinal analysis: 0.27-point increase [p = 0.006]) (22). However, it is possible that declining ovarian function is colinear with declining brain function, rather than contributory to it; further, since such studies cannot include comparator cohorts of men, the relative contributions of general aging and declining reproductive function to these findings have not been fully elucidated (31).
In addition to immunosenescence, another phenomenon that occurs with increasing age is a general, low-level increase in the production of proinflammatory cytokines (5). By promoting neuroinflammation, this process of “inflammaging” is thought to increase the risk of cognitive impairment in MS patients (5), which is one of the key symptoms that can overlap between menopause and MS (6).
Clinical Assessment and Care of Women With MS
Signs and Symptoms
Among MS patients, cognitive decline affects up to 65% of patients (32), and may include changes in memory, attention, executive function, information processing, and processing speed (33). Cognitive impairment in MS is of particular importance to menopausal patients as it has been consistently shown to worsen with older age (34, 35), despite no consistent evidence in the literature for different frequencies of cognitive problems between men and women with MS (34).
Relative to the general population, the prevalence of anxiety and depression is higher in patients with MS (36, 37), up to half of whom experience depression (38). In patients with MS, no consistent correlation has been established between increasing risk of depression and older age or female sex; indeed, almost half of the variance associated with rates of depression in MS is thought to reflect structural brain changes (5, 39). Nonetheless, certain factors may impart a particular vulnerability on the psychological well-being of menopausal women with MS. In some women undergoing the transition to menopause, declining estrogen levels may increase the risk of depression (40). Furthermore, given that many patients with MS develop a more progressive course after the age of 45 years (41), women may be grappling with not only the physical but also the psychological implications of this diagnosis at the time of menopause.
Of particular relevance to depression and anxiety, sleep disturbances are a common occurrence among healthy women in perimenopause (42). The prevalence of sleep dysfunction in patients with MS has been reported to be over 50%, which is substantially higher than in the general population, and it is more common in women with MS than in their male counterparts (43). Poor sleep patterns in patients with MS can result in cognitive impairments and changes in mood, with the link between poor sleep quality and depression and anxiety being particularly strong in women with MS (44). These disruptions in sleep have the potential to negatively impact other areas, such as decreasing quality of life and exacerbating comorbidities (43, 45). In particular, attentive management of factors such as sleep interruptions and depression may aid in reducing secondary fatigue, which may be modifiable in MS patients, in contrast to the primary fatigue thought to be caused by demyelination, inflammation, and axonal damage (46).
Urinary and sexual dysfunction are common occurrences in both menopausal women and in women with MS (47–50). Recent studies have investigated the potential influence of menopausal status on sexual dysfunction in women with MS. In a study of 248 women with MS, the rate of sexual dysfunction as measured by the Female Sexual Function Inventory (FSFI) was higher in postmenopausal (72/96 [75%]) than in premenopausal women (88/152 [58%]), albeit with no significant correlation found between menopausal status and FSFI subscales (51). In another study of 306 women, the proportion of postmenopausal women with MS with sexual dysfunction, as defined by FSFI score <26.55 and Female Sexual Distress Scale score >15, was 20/40 patients (50.0%). This proportion was higher than that among premenopausal women with MS (30/79 [37.9%]), but with the difference not reaching statistical significance (p = 0.24), and significantly higher than that for postmenopausal women without MS (16/57 [28.1%]; p = 0.03) (52).
In all women, the risk of osteoporosis and related fractures increases post menopause (53, 54). However, osteoporosis is more common in patients with MS compared with healthy populations; bone loss starts early during MS disease course, and increases as the disease progresses (55, 56). Moreover, there is evidence showing that chronic use of glucocorticosteroids reduces bone formation and is a risk factor for osteoporotic fractures (57), although data from studies in MS patients are conflicting (58–60). In a case-control study examining the association between MS and likelihood of developing osteopenia or osteoporosis, a total of 91 men (n = 45) and women (n = 46) with MS (mean [SD] age: 52.0 [10.3] years) had a total body bone mineral density of 1.12 g/cm2 and T-score of −0.6, indicating total bone density was not in the range of osteopenia or osteoporosis according to the World Health Organization classification. However, patients with MS in this analysis had bone density in the lumbar spine (bone density: 1.07 g/cm2; T-score: −1.09) and the left femoral hip (bone density: 0.69–0.86 g/cm2; T-score: −1.43 to −1.56) indicative of osteopenia, suggesting bone loss may be more prominent in certain areas of the body among MS patients (56). The North American Menopause Society recommends bone mineral density be tested in postmenopausal women who are at a higher risk of osteoporosis due to medical conditions, such as MS, and provides guidance for pharmaceutical management strategies (61).
Additionally, the risk of hypertension or cardiovascular comorbidities increases with age in both the general population and in patients with MS (62). In studies based on the North American Research Committee on Multiple Sclerosis Registry (N = 8,983), the presence of vascular comorbidities at MS diagnosis was associated with more severe disability at the time of MS diagnosis (odds ratio for moderate vs. mild disability: 1.51, 95% CI 1.12–2.05) (63), as well as higher risk of MS-related disability progression (hazard ratio per vascular condition for early gait disability: 1.51, 95% CI 1.41–1.61) (64). Cardiovascular comorbidities may also influence the relative benefits and risks of various DMTs. For example, secondary hypertension is linked to certain categories of DMTs including sphingosine-1-phosphate (S1P) inhibitors (e.g., fingolimod) (65–67) and teriflunomide.
Management of Menopausal Symptoms
Approaches for the management of menopausal symptoms include HT, herbal supplements available over the counter (e.g., soy and black cohosh), and off-label use of selective serotonin reuptake inhibitors (SSRIs) and anticonvulsants. HT includes estrogen therapy or combined estrogen-progestogen therapy, administered in both systemic (e.g., oral) and local (e.g., vaginal cream) formulations.
In MS, to date, little is known about the effect of HT on disease course. Research into the possible protective effects of HT on MS symptoms and overall well-being during the menopausal transition is of significant clinical importance. Few women observed in modern MS cohorts receive HT. For example, only 18.2% of the women observed in the Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital (CLIMB) study had used estrogen HT either alone or in combination with progesterone within 5 years of menopause (19). In an analysis of MS patients in the Nurses' Health Study (N = 248), a historical observational cohort, HT at the time of menopause was associated with better physical quality of life, as measured by the 10-item physical functioning assessment (PF10) subscale of the 36-Item Short Form Health Survey (p = 0.004) (68). However, this finding may not have reflected causality and could be explained by the fact that women with better physical quality of life are more likely to receive general preventative care (69, 70), including possible HT at the time that the cohort underwent menopause. Results from two interventional clinical trials assessing systemic exogenous estrogens in premenopausal women with MS are available. In a study of 164 women with relapsing-remitting MS (RRMS) aged 18–50 years who were receiving glatiramer acetate 20 mg, estriol treatment reduced the ARR over 2 years compared with placebo (adjusted rate ratio 0.63, 95% CI 0.37–1.05; p = 0.077) (71). Over 2 years in a randomized controlled trial of 150 women with RRMS aged 18–45 years, patients receiving interferon beta-1a (IFNB-1a) combined with ethinylestradiol 40 μg and desogestrel 125 μg as oral contraceptive showed a 26.5% reduction (p = 0.04) in the cumulative number of combined unique active lesions on brain magnetic resonance imaging (MRI), as well as a higher likelihood to be free from gadolinium-enhancing lesions (p = 0.03), compared with IFNB-1a alone (72). A post-hoc analysis of this study additionally reported a lower risk of cognitive impairment in the group who received ethinylestradiol 40 μg and desogestrel 125 μg combined with IFNB-1a, but also an increased risk of sexual dysfunction (p = 0.03 vs. IFNB-1a alone for both findings) (73). Results from a recently completed pilot trial in menopausal women are anticipated (NCT02710214).
In the general population, because of its superior efficacy, as well as some side effects associated with the other therapeutic options, HT is often the preferred therapy for treating menopausal symptoms. In a 2017 consensus statement, the North American Menopause Society concluded that HT remains the most effective treatment for menopausal vasomotor and genitourinary symptoms and may prevent bone loss and fracture (74). However, there are some risks, such as breast cancer, when progestogens are given concurrently with estrogens, as well as venous thrombosis despite a reduced risk of cardiovascular disease overall. Current interpretations of the results of the Women's Health Initiative do not support giving systemic estrogen therapy or estrogen-progestin therapy to prevent chronic diseases, including coronary heart disease and invasive breast cancer, even in young women, in the general population (75). With respect to neurological function, some observational studies have reported better cognition when HT was started within a 5-year window of the final menstrual period (76). However, interventional studies have yielded a more mixed picture (77, 78). The Women's Health Initiative administered HT to women well beyond their menopausal transition, and reported increased risk of stroke and dementia (79). Recent re-analyses of women within a narrower postmenopausal window have been more reassuring, and there are no cognitive contraindications to HT for menopausal women experiencing vasomotor symptoms (74).
In women for whom HT is contraindicated (e.g., prior breast cancer or personal preference), there are other treatment options for menopausal symptoms. For example, for the treatment of vasomotor symptoms, SSRIs, norepinephrine reuptake inhibitors, and anticonvulsants have demonstrated greater efficacy vs. placebo (80–83). Although side effects with SSRIs are typically short lived, those experienced with anticonvulsants may be more severe and are therefore a limiting factor in their use within the perimenopausal/menopausal population (42, 84). Trials of herbal remedies have shown no significant effects on vasomotor symptoms compared with placebo (85). As an approach for bone density preservation, the use of alendronate might be recommended. In the overlap of bladder symptoms due to menopause and MS, intravesical botulinum toxin and pelvic floor therapy may be effective (86), especially in women in whom HT should be avoided and who might also have contraindication to anticholinergics due to the potential to worsen cognitive function. Finally, addressing sleep disturbances early on, may aid in avoiding subsequent chronic sleep problems. When introducing symptomatic therapies, it is important to consider overall safety and any possible pharmacological side effects or interactions. For example, lower doses of sleeping agents such as zolpidem are recommended in women than in men.
Regional and Societal Differences
Research in MS, including the effects of menopause, on symptoms, neurological function, and quality of life are often carried out in White women from Western cultures. The extent to which findings on menopause can be translated to women from other racial and ethnic groups, as well as different countries or continents, is unknown (87, 88). Lock and Kaufert reported lower rates of menopause-associated symptoms, including hot flashes, sleep disturbances, and low mood, in women from Japan compared with women from the United States and Canada, and comparable rates to those reported in China and Thailand. Additionally, in these populations, the postmenopausal period could entail different risks for chronic diseases (88). Results from the Study of Women's Health Across the Nation, which included 14,906 middle-aged women from across the United States, showed increased psychosomatic symptoms reported in White women and greater vasomotor symptoms reported in African American women vs. other racial and ethnic populations (87). These findings highlight the need to consider not only genetic, but also physiological, social, and cultural factors in studies of menopause and MS.
Recommended Screenings for Menopausal MS Patients
Women with MS undergoing the menopausal transition may experience symptoms from menopause-associated physiological changes, MS disability progression, and age-associated comorbidities simultaneously, making it important to proactively consider multifactorial causes of worsening symptoms or function at menopause.
Early and appropriate screenings for comorbidities associated with menopause and MS are, therefore, recommended. Screenings should include, but are not limited to, blood pressure, cancer, and bone density screenings, including assessments for confounding behavioral factors such as smoking. Neglected cancer screenings in patients with MS have the potential to impact mortality, and effort to rule out cancer should therefore be undertaken whenever symptoms suggest the possibility of causality outside the general scope of MS (70). Similarly, evaluating for and preventing osteoporosis through appropriate bone density screenings could partially reduce the increased bone fracture risk in MS patients (53, 54), who are also at risk of falls. As smoking can differentially impact pre- vs. postmenopausal women, it is important to determine whether such a confounding factor may be contributing to loss of bone density. Whenever possible, smoking cessation should be encouraged as a means of reducing risk for bone fracture (61).
Author Recommendations
Table 1 provides a summary of recommendations and features for neurologists and other health care professionals for the care of menopausal women with MS.
Table 1. Summary of author recommendations for neurologists and other health care professionals.
Conclusion
For professionals to effectively manage and care for the female MS population regardless of age, more research is required to disentangle the effects of menopause on symptoms and the disease course in patients with MS. Further longitudinal studies on MS disease activity in diverse populations of women with MS are needed. Of specific interest will be more randomized controlled clinical trials to investigate the possible protective effect of HT on women with MS, and to investigate the benefit-to-risk ratio in this population, which may differ from the general population. In addition, available information regarding DMTs in postmenopausal women with MS is currently limited, as clinical trials in MS often restrict enrollment to those aged ≤ 50 or ≤ 55 years. To provide for evidence-based decisions in an older patient population, trial designs should aim to include patients who are aged >50 years. Enhanced understanding of the relationship between sex steroids, menopause and immunosenescence may also provide new opportunities for management of MS in women. Interventions and treatments, as well as guidance and support, are needed for patients who may be particularly vulnerable to physiological and psychological decline at this time point in their lives, and beyond.
Author Contributions
RB, AO, MH, BE-H, AL, KH, and EKH provided conception, critical review and revision, and final approval of the manuscript for submission. All authors contributed to the article and approved the submitted version.
Funding
Medical writing support under the direction of the authors was provided by Beth Fisher, PhD, and Laura Geuss, PhD (Onyx, Knutsford, UK), funded by Sanofi. Additional editorial support was provided by Elevate Scientific Solutions. EKH has been supported by PROGRES Q27/LF1 (Czech Ministry of Education). The manuscript was reviewed for scientific accuracy by Darren P. Baker, PhD, Jonathan Valenzano, PharmD, and Karyn Liu, PhD, of Sanofi. The authors were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.
Conflict of Interest
RB reports consultancy fees from Alexion, Biogen, EMD Serono, Novartis, Roche Genentech, and Sanofi Genzyme; and research support from Akili Interactive and Roche Genentech. AO reports consulting fees from Biogen, Bristol Myers Squibb, EMD Serono, Roche Genentech, and Sanofi Genzyme; and research support from Alexion, Novartis, Roche Genentech, and Sanofi Genzyme. MH reports consulting fees from Biogen, Genentech, Genzyme, Serono, and Teva; and research and support from Biogen, Genzyme, and Serono. BE-H reports research support, consultancy fees, speaker fees, and personal compensation for activities with Almirall, Bayer HealthCare, Biogen, MedDay, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. AL has served as a Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations or speaker honoraria from Biogen, Merck, Mylan, Novartis, Sanofi Genzyme, Teva, and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis. KH reports consultancy fees, speaker fees, and research support from Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. EKH reports speaker honoraria and research grant support from Actelion, Biogen, Celgene, Merck Serono, Novartis, Sanofi Genzyme, and Teva; compensation for advisory board activities from Actelion, Biogen, Celgene, Genzyme, and Novartis; and support from the Czech Ministry of Education, Project PROGRES Q27/LF1.
Abbreviations
AMH, anti-Müllerian hormone; ARR, annualized relapse rate; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; FSFI, Female Sexual Function Inventory; HT, hormone therapy; IFNB-1a, interferon beta-1a; MS, multiple sclerosis; RRMS, relapsing-remitting MS; SSRI, selective serotonin reuptake inhibitor.
References
1. Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. (2006) 52:61–76. doi: 10.1016/j.neuron.2006.09.011
2. Wallin MT, Culpepper WJ, Coffman P, Pulaski S, Maloni H, Mahan CM, et al. The Gulf War era multiple sclerosis cohort: age and incidence rates by race, sex and service. Brain. (2012) 135:1778–85. doi: 10.1093/brain/aws099
3. Sanai SA, Saini V, Benedict RH, Zivadinov R, Teter BE, Ramanathan M, et al. Aging and multiple sclerosis. Mult Scler. (2016) 22:717–25. doi: 10.1177/1352458516634871
4. Koch-Henriksen N, Thygesen LC, Stenager E, Laursen B, Magyari M. Incidence of MS has increased markedly over six decades in Denmark particularly with late onset and in women. Neurology. (2018) 90:e1954–63. doi: 10.1212/WNL.0000000000005612
5. Musella A, Gentile A, Rizzo FR, De Vito F, Fresegna D, Bullitta S, et al. Interplay between age and neuroinflammation in multiple sclerosis: effects on motor and cognitive functions. Front Aging Neurosci. (2018) 10:238. doi: 10.3389/fnagi.2018.00238
6. Bove R, Vaughan T, Chitnis T, Wicks P, De Jager PL. Women's experiences of menopause in an online MS cohort: a case series. Mult Scler Relat Disord. (2016) 9:56–9. doi: 10.1016/j.msard.2016.06.015
7. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group. N Engl J Med. (1998) 339:285–91. doi: 10.1056/NEJM199807303390501
8. Gold SM, Voskuhl RR. Estrogen treatment in multiple sclerosis. J Neurol Sci. (2009) 286:99–103. doi: 10.1016/j.jns.2009.05.028
9. Rocca WA, Grossardt BR, Shuster LT. Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity. Brain Res. (2011) 1379:188–98. doi: 10.1016/j.brainres.2010.10.031
10. Mackenzie-Graham AJ, Rinek GA, Avedisian A, Morales LB, Umeda E, Boulat B, et al. Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis. J Neurosci Res. (2012) 90:1310–23. doi: 10.1002/jnr.23019
11. D'hooghe MB, Haentjens P, Nagels G, D'hooghe T, De Keyser J. Menarche, oral contraceptives, pregnancy and progression of disability in relapsing onset and progressive onset multiple sclerosis. J Neurol. (2012) 259:855–61. doi: 10.1007/s00415-011-6267-7
12. Sena A, Couderc R, Vasconcelos JC, Ferret-Sena V, Pedrosa R. Oral contraceptive use and clinical outcomes in patients with multiple sclerosis. J Neurol Sci. (2012) 317:47–51. doi: 10.1016/j.jns.2012.02.033
13. Gava G, Bartolomei I, Costantino A, Berra M, Venturoli S, Salvi F, et al. Long-term influence of combined oral contraceptive use on the clinical course of relapsing-remitting multiple sclerosis. Fertil Steril. (2014) 102:116–22. doi: 10.1016/j.fertnstert.2014.03.054
14. Smith R, Studd JW. A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J R Soc Med. (1992) 85:612–3.
15. Ferrell RJ, O'connor KA, Rodríguez G, Gorrindo T, Holman DJ, Brindle E, et al. Monitoring reproductive aging in a 5-year prospective study: aggregate and individual changes in steroid hormones and menstrual cycle lengths with age. Menopause. (2005) 12:567–77. doi: 10.1097/01.gme.0000172265.40196.86
16. Kelsey TW, Wright P, Nelson SM, Anderson RA, Wallace WH. A validated model of serum anti-Müllerian hormone from conception to menopause. PLoS ONE. (2011) 6:e22024. doi: 10.1371/journal.pone.0022024
17. Depmann M, Broer SL, Van Der Schouw YT, Tehrani FR, Eijkemans MJ, Mol BW, et al. Can we predict age at natural menopause using ovarian reserve tests or mother's age at menopause? A systematic literature review. Menopause. (2016) 23:224–32. doi: 10.1097/GME.0000000000000509
18. Bove R, Healy BC, Secor E, Vaughan T, Katic B, Chitnis T, et al. Patients report worse MS symptoms after menopause: findings from an online cohort. Mult Scler Relat Disord. (2015) 4:18–24. doi: 10.1016/j.msard.2014.11.009
19. Bove R, Healy BC, Musallam A, Glanz BI, De Jager PL, Chitnis T. Exploration of changes in disability after menopause in a longitudinal multiple sclerosis cohort. Mult Scler. (2016) 22:935–43. doi: 10.1177/1352458515606211
20. Gold EB, Bromberger J, Crawford S, Samuels S, Greendale GA, Harlow SD, et al. Factors associated with age at natural menopause in a multiethnic sample of midlife women. Am J Epidemiol. (2001) 153:865–74. doi: 10.1093/aje/153.9.865
21. Thöne J, Kollar S, Nousome D, Ellrichmann G, Kleiter I, Gold R, et al. Serum anti-Müllerian hormone levels in reproductive-age women with relapsing-remitting multiple sclerosis. Mult Scler. (2015) 21:41–7. doi: 10.1177/1352458514540843
22. Graves JS, Henry RG, Cree BAC, Lambert-Messerlian G, Greenblatt RM, Waubant E, et al. Ovarian aging is associated with gray matter volume and disability in women with MS. Neurology. (2018) 90:e254–60. doi: 10.1212/WNL.0000000000004843
23. Baroncini D, Annovazzi PO, De Rossi N, Mallucci G, Torri Clerici V, Tonietti S, et al. Impact of natural menopause on multiple sclerosis: a multicentre study. J Neurol Neurosurg Psychiatry. (2019) 90:1201–6. doi: 10.1136/jnnp-2019-320587
24. Ladeira F, Salavisa M, Caetano A, Barbosa R, Sa F, Correia AS. The influence of menopause in multiple sclerosis course: a longitudinal cohort study. Eur Neurol. (2018) 80:223–7. doi: 10.1159/000496374
25. Karageorgiou V, Lambrinoudaki I, Goulis DG. Menopause in women with multiple sclerosis: a systematic review. Maturitas. (2020) 135:68–73. doi: 10.1016/j.maturitas.2020.03.001
26. Ostan R, Monti D, Gueresi P, Bussolotto M, Franceschi C, Baggio G. Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine. Clin Sci. (2016) 130:1711–25. doi: 10.1042/CS20160004
27. Bolton C, Smith PA. The influence and impact of ageing and immunosenescence (ISC) on adaptive immunity during multiple sclerosis (MS) and the animal counterpart experimental autoimmune encephalomyelitis (EAE). Ageing Res Rev. (2018) 41:64–81. doi: 10.1016/j.arr.2017.10.005
28. Bove R. Autoimmune diseases and reproductive aging. Clin Immunol. (2013) 149:251–64. doi: 10.1016/j.clim.2013.02.010
29. Vrachnis N, Zygouris D, Iliodromiti Z, Daniilidis A, Valsamakis G, Kalantaridou S. Probing the impact of sex steroids and menopause-related sex steroid deprivation on modulation of immune senescence. Maturitas. (2014) 78:174–8. doi: 10.1016/j.maturitas.2014.04.014
30. Giefing-Kröll C, Berger P, Lepperdinger G, Grubeck-Loebenstein B. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell. (2015) 14:309–21. doi: 10.1111/acel.12326
31. Ysrraelit MC, Correale J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology. (2019) 156:9–22. doi: 10.1111/imm.13004
32. Feinstein A, Deluca J, Baune BT, Filippi M, Lassman H. Cognitive and neuropsychiatric disease manifestations in MS. Mult Scler Relat Disord. (2013) 2:4–12. doi: 10.1016/j.msard.2012.08.001
33. Chiaravalloti ND, Deluca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. (2008) 7:1139–51. doi: 10.1016/S1474-4422(08)70259-X
34. Ruano L, Portaccio E, Goretti B, Niccolai C, Severo M, Patti F, et al. Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes. Mult Scler. (2017) 23:1258–67. doi: 10.1177/1352458516674367
35. Amato MP, Prestipino E, Bellinvia A, Niccolai C, Razzolini L, Pastò L, et al. Cognitive impairment in multiple sclerosis: An exploratory analysis of environmental and lifestyle risk factors. PLoS ONE. (2019) 14:e0222929. doi: 10.1371/journal.pone.0222929
36. Chwastiak LA, Ehde DM. Psychiatric issues in multiple sclerosis. Psychiatr Clin North Am. (2007) 30:803–17. doi: 10.1016/j.psc.2007.07.003
37. Boeschoten RE, Braamse AMJ, Beekman ATF, Cuijpers P, Van Oppen P, Dekker J, et al. Prevalence of depression and anxiety in multiple sclerosis: a systematic review and meta-analysis. J Neurol Sci. (2017) 372:331–41. doi: 10.1016/j.jns.2016.11.067
38. Feinstein A. Multiple sclerosis and depression. Mult Scler. (2011) 17:1276–81. doi: 10.1177/1352458511417835
39. Feinstein A, Magalhaes S, Richard JF, Audet B, Moore C. The link between multiple sclerosis and depression. Nat Rev Neurol. (2014) 10:507–17. doi: 10.1038/nrneurol.2014.139
40. Schmidt PJ. Depression, the perimenopause, and estrogen therapy. Ann N Y Acad Sci. (2005) 1052:27–40. doi: 10.1196/annals.1347.003
41. Tutuncu M, Tang J, Zeid NA, Kale N, Crusan DJ, Atkinson EJ, et al. Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler. (2013) 19:188–98. doi: 10.1177/1352458512451510
42. Kravitz HM, Joffe H. Sleep during the perimenopause: a SWAN story. Obstet Gynecol Clin North Am. (2011) 38:567–86. doi: 10.1016/j.ogc.2011.06.002
43. Bamer AM, Johnson KL, Amtmann D, Kraft GH. Prevalence of sleep problems in individuals with multiple sclerosis. Mult Scler. (2008) 14:1127–30. doi: 10.1177/1352458508092807
44. Vitkova M, Rosenberger J, Gdovinova Z, Szilasiova J, Mikula P, Groothoff JW, et al. Poor sleep quality in patients with multiple sclerosis: gender differences. Brain Behav. (2016) 6:e00553. doi: 10.1002/brb3.553
45. Merlino G, Fratticci L, Lenchig C, Valente M, Cargnelutti D, Picello M, et al. Prevalence of ‘poor sleep’ among patients with multiple sclerosis: an independent predictor of mental and physical status. Sleep Med. (2009) 10:26–34. doi: 10.1016/j.sleep.2007.11.004
46. Ghajarzadeh M, Jalilian R, Eskandari G, Sahraian MA, Azimi A, Mohammadifar M. Fatigue in multiple sclerosis: relationship with disease duration, physical disability, disease pattern, age and sex. Acta Neurol Belg. (2013) 113:411–4. doi: 10.1007/s13760-013-0198-2
47. De Sèze M, Ruffion A, Denys P, Joseph PA, Perrouin-Verbe B. The neurogenic bladder in multiple sclerosis: review of the literature and proposal of management guidelines. Mult Scler. (2007) 13:915–28. doi: 10.1177/1352458506075651
48. Calleja-Agius J, Brincat MP. The urogenital system and the menopause. Climacteric. (2015) 18:18–22. doi: 10.3109/13697137.2015.1078206
49. Faubion SS, Rullo JE. Sexual dysfunction in women: a practical approach. Am Fam Phys. (2015) 92:281–8.
50. Caretto M, Giannini A, Russo E, Simoncini T. Preventing urinary tract infections after menopause without antibiotics. Maturitas. (2017) 99:43–6. doi: 10.1016/j.maturitas.2017.02.004
51. Konstantinidis C, Tzitzika M, Bantis A, Nikolia A, Samarinas M, Kratiras Z, et al. Female sexual dysfunction among Greek women with multiple sclerosis: correlations with organic and psychological factors. Sex Med. (2019) 7:19–25. doi: 10.1016/j.esxm.2018.11.003
52. Gava G, Visconti M, Salvi F, Bartolomei I, Seracchioli R, Meriggiola MC. Prevalence and psychopathological determinants of sexual dysfunction and related distress in women with and without multiple sclerosis. J Sex Med. (2019) 16:833–42. doi: 10.1016/j.jsxm.2019.03.011
53. Hearn AP, Silber E. Osteoporosis in multiple sclerosis. Mult Scler. (2010) 16:1031–43. doi: 10.1177/1352458510368985
54. Bove R, Chitnis T, Houtchens M. Menopause in multiple sclerosis: therapeutic considerations. J Neurol. (2014) 261:1257–68. doi: 10.1007/s00415-013-7131-8
55. Murphy O, Zandi MS, Lindenberg N, Murphy E, Chataway J. Bone health in patients with multiple sclerosis relapses. Mult Scler Relat Disord. (2016) 6:75–80. doi: 10.1016/j.msard.2016.02.003
56. Simonsen CS, Celius EG, Brunborg C, Tallaksen C, Eriksen EF, Holmøy T, et al. Bone mineral density in patients with multiple sclerosis, hereditary ataxia or hereditary spastic paraplegia after at least 10 years of disease - a case control study. BMC Neurol. (2016) 16:252. doi: 10.1186/s12883-016-0771-4
57. Weinstein RS. Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinol Metab Clin North Am. (2012) 41:595–611. doi: 10.1016/j.ecl.2012.04.004
58. Schwid SR, Goodman AD, Puzas JE, Mcdermott MP, Mattson DH. Sporadic corticosteroid pulses and osteoporosis in multiple sclerosis. Arch Neurol. (1996) 53:753–7. doi: 10.1001/archneur.1996.00550080071014
59. Tüzün S, Altintaş A, Karacan I, Tangürek S, Saip S, Siva A. Bone status in multiple sclerosis: beyond corticosteroids. Mult Scler. (2003) 9:600–4. doi: 10.1191/1352458503ms966oa
60. Zengin Karahan S, Boz C, Kilic S, Can Usta N, Ozmenoglu M, Altunayoglu Cakmak V, et al. Lack of association between pulse steroid therapy and bone mineral density in patients with multiple sclerosis. Mult Scler Int. (2016) 2016:5794910. doi: 10.1155/2016/5794910
61. The North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. (2010) 17:25–54. doi: 10.1097/gme.0b013e3181c617e6
62. Marrie RA, Fisk J, Tremlett H, Wolfson C, Warren S, Blanchard J, et al. Differing trends in the incidence of vascular comorbidity in MS and the general population. Neurol Clin Pract. (2016) 6:120–8. doi: 10.1212/CPJ.0000000000000230
63. Marrie RA, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity delays diagnosis and increases disability at diagnosis in MS. Neurology. (2009) 72:117–24. doi: 10.1212/01.wnl.0000333252.78173.5f
64. Marrie RA, Rudick R, Horwitz R, Cutter G, Tyry T, Campagnolo D, et al. Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology. (2010) 74:1041–7. doi: 10.1212/WNL.0b013e3181d6b125
65. Laroni A, Brogi D, Brescia Morra V, Guidi L, Pozzilli C, Comi G, et al. Safety and tolerability of fingolimod in patients with relapsing-remitting multiple sclerosis: results of an open-label clinical trial in Italy. Neurol Sci. (2017) 38:53–9. doi: 10.1007/s10072-016-2701-z
66. Meissner A, Miro F, Jimenez-Altayo F, Jurado A, Vila E, Planas AM. Sphingosine-1-phosphate signalling-a key player in the pathogenesis of Angiotensin II-induced hypertension. Cardiovasc Res. (2017) 113:123–33. doi: 10.1093/cvr/cvw256
67. Iwazu Y, Muto S, Ioka T, Watanabe Y, Iwazu K, Kusano E, et al. Multiple sclerosis drug fingolimod induces thrombotic microangiopathy in deoxycorticosterone acetate/salt hypertension. Hypertension. (2018) 72:776–84. doi: 10.1161/HYPERTENSIONAHA.117.10655
68. Bove R, White CC, Fitzgerald KC, Chitnis T, Chibnik L, Ascherio A, et al. Hormone therapy use and physical quality of life in postmenopausal women with multiple sclerosis. Neurology. (2016) 87:1457–63. doi: 10.1212/WNL.0000000000003176
69. Andresen EM, Peterson-Besse JJ, Krahn GL, Walsh ES, Horner-Johnson W, Iezzoni LI. Pap, mammography, and clinical breast examination screening among women with disabilities: a systematic review. Womens Health Issues. (2013) 23:e205–14. doi: 10.1016/j.whi.2013.04.002
70. Dobos K, Healy B, Houtchens M. Access to preventive health care in severely disabled women with multiple sclerosis. Int J MS Care. (2015) 17:200–5. doi: 10.7224/1537-2073.2013-046
71. Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. (2016) 15:35–46. doi: 10.1016/S1474-4422(15)00322-1
72. Pozzilli C, De Giglio L, Barletta VT, Marinelli F, Angelis FD, Gallo V, et al. Oral contraceptives combined with interferon β in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. (2015) 2:e120. doi: 10.1212/NXI.0000000000000120
73. De Giglio L, Marinelli F, Barletta VT, Pagano VA, De Angelis F, Fanelli F, et al. Effect on cognition of estroprogestins combined with interferon beta in multiple sclerosis: analysis of secondary outcomes from a randomised controlled trial. CNS Drugs. (2017) 31:161–8. doi: 10.1007/s40263-016-0401-0
74. The North American Menopause Society. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. (2017) 24:728–53. doi: 10.1097/GME.0000000000000921
75. Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. (2013) 310:1353–68. doi: 10.1001/jama.2013.278040
76. Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA, et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology. (2014) 82:222–9. doi: 10.1212/WNL.0000000000000033
77. Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS-cognitive and affective study. PLoS Med. (2015) 12:e1001833. doi: 10.1371/journal.pmed.1001833
78. Kantarci K, Tosakulwong N, Lesnick TG, Zuk SM, Lowe VJ, Fields JA, et al. Brain structure and cognition 3 years after the end of an early menopausal hormone therapy trial. Neurology. (2018) 90:e1404–12. doi: 10.1212/WNL.0000000000005325
79. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. (2003) 289:2651–62. doi: 10.1001/jama.289.20.2651
80. Archer DF, Dupont CM, Constantine GD, Pickar JH, Olivier S, Study I. Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safety. Am J Obstet Gynecol. (2009) 200:238.e1–10. doi: 10.1016/j.ajog.2008.10.057
81. Archer DF, Seidman L, Constantine GD, Pickar JH, Olivier S. A double-blind, randomly assigned, placebo-controlled study of desvenlafaxine efficacy and safety for the treatment of vasomotor symptoms associated with menopause. Am J Obstet Gynecol. (2009) 200:172.e1–10. doi: 10.1016/j.ajog.2008.09.877
82. Hall E, Frey BN, Soares CN. Non-hormonal treatment strategies for vasomotor symptoms: a critical review. Drugs. (2011) 71:287–304. doi: 10.2165/11585360-000000000-00000
83. Joffe H, Guthrie KA, Lacroix AZ, Reed SD, Ensrud KE, Manson JE, et al. Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial. JAMA Intern Med. (2014) 174:1058–66. doi: 10.1001/jamainternmed.2014.1891
84. Hill DA, Crider M, Hill SR. Hormone therapy and other treatments for symptoms of menopause. Am Fam Phys. (2016) 94:884–9.
85. Johnson A, Roberts L, Elkins G. Complementary and alternative medicine for menopause. J Evid Based Integr Med. (2019) 24:2515690x19829380. doi: 10.1177/2515690X19829380
86. Çetinel B, Tarcan T, Demirkesen O, Özyurt C, Sen I, Erdogan S, et al. Management of lower urinary tract dysfunction in multiple sclerosis: a systematic review and Turkish consensus report. Neurourol Urodyn. (2013) 32:1047–57. doi: 10.1002/nau.22374
87. Avis NE, Stellato R, Crawford S, Bromberger J, Ganz P, Cain V, et al. Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups. Soc Sci Med. (2001) 52:345–56. doi: 10.1016/S0277-9536(00)00147-7
88. Lock M, Kaufert P. Menopause, local biologies, and cultures of aging. Am J Hum Biol. (2001) 13:494–504. doi: 10.1002/ajhb.1081
89. Kuhl H. Breast cancer risk in the WHI study: the problem of obesity. Maturitas. (2005) 51:83–97. doi: 10.1016/j.maturitas.2005.02.018
90. Fournier A, Dossus L, Mesrine S, Vilier A, Boutron-Ruault MC, Clavel-Chapelon F, et al. Risks of endometrial cancer associated with different hormone replacement therapies in the E3N cohort, 1992-2008. Am J Epidemiol. (2014) 180:508–17. doi: 10.1093/aje/kwu146
91. Stute P, Neulen J, Wildt L. The impact of micronized progesterone on the endometrium: a systematic review. Climacteric. (2016) 19:316–28. doi: 10.1080/13697137.2016.1187123
92. Holmqvist P, Hammar M, Landtblom AM, Brynhildsen J. Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosis. Fertil Steril. (2010) 94:2835–7. doi: 10.1016/j.fertnstert.2010.06.045
93. Bove R. Women's issues in multiple sclerosis. Semin Neurol. (2016) 36:154–62. doi: 10.1055/s-0036-1579736
94. Mills EA, Mao-Draayer Y. Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients. Mult Scler. (2018) 24:1014–22. doi: 10.1177/1352458518775550
95. Barrett MW, Roberts B. Preventative screening in people with multiple sclerosis. Int J MS Care. (2010) 12:168–76. doi: 10.7224/1537-2073-12.4.168
96. Grzegorski T, Losy J. Cognitive impairment in multiple sclerosis - a review of current knowledge and recent research. Rev Neurosci. (2017) 28:845–60. doi: 10.1515/revneuro-2017-0011
97. Rankin K, Bove R. Caring for women with multiple sclerosis across the lifespan. Curr Neurol Neurosci Rep. (2018) 18:36. doi: 10.1007/s11910-018-0846-2
Keywords: multiple sclerosis, menopause, hormone therapy, best practices, fatigue, cognition
Citation: Bove R, Okai A, Houtchens M, Elias-Hamp B, Lugaresi A, Hellwig K and Kubala Havrdová E (2021) Effects of Menopause in Women With Multiple Sclerosis: An Evidence-Based Review. Front. Neurol. 12:554375. doi: 10.3389/fneur.2021.554375
Received: 21 April 2020; Accepted: 17 February 2021;
Published: 19 March 2021.
Edited by:
Brian M. Sandroff, Kessler Foundation, United StatesReviewed by:
Rachel Bollaert, Marquette University, United StatesMelinda Magyari, Danish Multiple Sclerosis Center (DMSC), Denmark
Copyright © 2021 Bove, Okai, Houtchens, Elias-Hamp, Lugaresi, Hellwig and Kubala Havrdová. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Riley Bove, riley.bove@ucsf.edu