The Protective Role of Vitamin D and Oxytocin in Breastfeeding Multiple Sclerosis Patients

Introduction

Multiple sclerosis is a neurological disease which disproportionately affects more women than men worldwide. There is no cure for the disease, with existing treatments only serving to manage symptoms and slow down progression of the disease. However, researchers have found that the rate of MS relapses falls dramatically in breastfeeding patients, suggesting that breastfeeding could have a protective effect against MS. It is unclear why this is. In this blog post, we put forward our ideas as to why breastfeeding women are protected against MS relapse.

What is multiple sclerosis?

Multiple Sclerosis (MS) is a neurological autoimmune disease of the brain and spinal cord. In MS, inflammatory T cells attack the myelin sheath which protects neurons (nerve cells) in the brain and spinal cord (Cao, 2016). This demyelination results in the interruption of signals between the nerves and the brain (Figure 1).
MS affects over 2 million people worldwide and is more common in females; women are three times more likely to develop MS than men (Almas et al., 2016).

Symptoms of MS (as described by MS Society, n.d.) include:

1. Numbness or tingling in various parts of the body
2. Fatigue
3. Muscle cramps, spasms, and stiffness
4. Feeling dizzy
5. Inability to walk
6. Speech problems

The causes of MS are unknown, but there are certain factors associated with increased likelihood of developing the disease. These include smoking, a family history of MS, being between the ages of 20 and 50, previous infection with the Epstein-Barr virus and vitamin D deficiency (Nourbaksh, 2019).

Figure 1. Comparison of a healthy neuron and a neuron affected by Multiple Sclerosis.

Hormonal changes during pregnancy and breastfeeding

Women who breastfeed are almost half as likely to suffer a relapse in MS compared to women who don’t breastfeed after giving birth (Almas et al., 2016) (Krysko et al., 2020). However, it is unclear exactly why this is.
During pregnancy and breastfeeding, there are four main hormones involved: prolactin, progesterone, oestrogen and oxytocin (Geneva: World Health Organization, 2009). As shown in Figure 2, Progesterone and oestrogen levels increase during pregnancy and decline after childbirth (post-partum) (Geneva: World Health Organization, 2009). Prolactin and oxytocin secretion also increase during pregnancy, before rapidly rising during breastfeeding (Geneva: World Health Organization, 2009).

During the third semester of pregnancy, there is also a reduction in MS relapses (Varytė, G. et al. 2020). In pregnant women, the immune response is altered to protect the fetal-placental unit (Collorone, Kodali and Toosy, 2022). Inflammatory Th-1 cells are suppressed by high levels of oestrogen (estradiol) and progesterone (Collorone, Kodali and Toosy, 2022). It is possible that this could also reduce MS inflammatory activity (Collorone, Kodali and Toosy, 2022) (Kunkl, M. et al., 2020) (Hierweger. A.M. et al. 2020) (Kipp et al., 2012). Therefore, hormonal changes during pregnancy (namely, the rise in progesterone and oestrogen) could explain why studies have shown a reduction in MS relapses during the third semester of pregnancy (Varytė, G. et al., 2020) (Geneva: World Health Organization, 2009).

Meanwhile, prolactin and oxytocin are the two main hormones that directly affect breastfeeding; oestrogen is also indirectly involved in lactation (Geneva: World Health Organization, 2009). Prolactin and oxytocin secretion increases during lactation (Figure 2). Rasmi et al. (2023) found that prolactin can increase inflammatory immune responses, and MS has been associated with elevated prolactin levels (Türkoğlu et al. 2016). (Friuli et al., 2021) (Brand, 2004). Oxytocin is a hormone with anti-neuroinflammatory effects, which may relieve MS symptoms (Friuli et al., 2021). It has been found that oxytocin prevents T cells from attacking self-antigens, which would include myelin (Mehdi, S. F. et al. 2022).

Since oxytocin and prolactin have opposite effects on MS disease severity, we suspect that additional factors could contribute to the decrease in MS relapses observed in breastfeeding women.

Figure 2. Increase/Decrease in Hormone Levels Throughout Pregnancy and Breastfeeding.

Vitamin D and its link to autoimmune diseases

Vitamin D is a steroid hormone that plays a crucial role in regulating the immune response. Low vitamin D levels have been linked to an increased risk of developing autoimmune diseases (Dupuis et al, 2021) (Athanassiou, L. et al., 2023). Vitamin D deficiency in early life is also linked to the development of autoimmune diseases: a recent study found that T cells in mice with vitamin D deficiency later initiated an auto-immune response against healthy tissues (Artusa et al. 2024).

For decades, it has been suspected that vitamin D could have a potential therapeutic effect in tuberculosis, while vitamin D deficiency has been linked with the development of autoimmune rheumatic diseases (Cutolo, 2008). Because of this, it has been suggested that vitamin D has a protective role in autoimmune diseases (Athanassiou, L. et al., 2023). Research has already shown that vitamin D supplementation may benefit some MS patients (Sintzel, Rametta and Reder, 2017).

Vitamin D, in its active form, binds with vitamin D receptors on immune cells including T cells and dendritic cells. Dendritic cells control T cell activity. Vitamin D causes dendritic cells to release anti-inflammatory cytokine, IL-10 (Athanassiou et al. 2023), which results in reduced T cell proliferation and increased T cell maturation (Figure 3). Consequently, inflammatory cytokine (IFN-γ, TNF) production decreases and more anti-inflammatory cytokines (IL-4, IL-10) are released by T cells (Vassiliou et al. (2021). Therefore, vitamin D suppresses the inflammatory immune response, which means that vitamin D could be used to treat multiple sclerosis.

Figure 3. Effects of Vitamin D on T cells, according to Vassiliou et al. (2021).

Vitamin D levels during breastfeeding – research lacking

Whereas there is evidence on the protective effect of vitamin D in multiple sclerosis, surprisingly, there are few available data on vitamin D levels in breastfeeding women in comparison to non-breastfeeding women and non-pregnant women (Gellert, S.,Ströhle, A., Hahn, A., 2017). Existing research on how vitamin D levels are affected by breastfeeding is not conclusive. It has been suggested that vitamin D levels may decline during breastfeeding due to the transfer of vitamin D from mother to infant in the form of breast milk (Narchi et al., 2010). However, one study found that only 26.6% of breastfeeding women were vitamin D-deficient (Gellert, S., Ströhle, A., Hahn, A., 2017). In addition, the authors noted that breastfeeding mothers in the study may have already been deficient in vitamin D prior to breastfeeding (Gellert, S., Ströhle, A., Hahn, A., 2017).

Elsewhere, vitamin D deficiency in pregnant women was reported to range from 0 to 27%, in contrast with 0-41% in non-pregnant women (Aparecida da Silveira et al., 2022). However, this study did not include breastfeeding women (Aparecida da Silveira et al., 2022). Adding to the uncertainty, the definitions of ‘healthy’ and ‘deficient’ vitamin D levels can vary between studies and are not standardised (Gellert, S., Ströhle, A., Hahn, A., 2017). It is possible that vitamin D levels could be higher post-partum in breastfeeding women than in non-breastfeeding women, despite being below ‘sufficient’ levels in both groups of women (Gellert, S., Ströhle, A., Hahn, A., 2017) (Aparecida da Silveira et al., 2022). More research is needed to determine conclusively how vitamin D levels change during breastfeeding.

Vitamin D impact on MS relapses during breastfeeding

Only a handful of studies have been published on vitamin D levels in breastfeeding multiple sclerosis patients. Existing studies have contained only small groups; results obtained from small patient groups are not as reliable as results from larger studies.

Jalkanen et al. (2014) found that vitamin D levels rise continuously over the duration of pregnancy. This rise in vitamin D could be a factor in the reduction of MS relapses seen in the third semester of pregnancy reported by Varytė, G. et al. (2020), among other studies. In addition, vitamin D levels during breastfeeding were similar to early pregnancy levels (Jalkanen et al. 2014), when anti-inflammatory hormones progesterone and oestrogen are elevated (Figure 2). The fact that vitamin D levels were at a similar, elevated, level during breastfeeding and early pregnancy, indicates that other factors may influence the reduction in MS relapses during breastfeeding, in combination with vitamin D, since progesterone and oestrogen levels fall during breastfeeding.

Langer-Gould et al. found that low vitamin D during breastfeeding was not in isolation a significant cause of MS relapse in pregnant women (Langer-Gould, et al., 2010). Breastfeeding was “strongly associated” with low vitamin D levels (Langer-Gould, et al., 2010). However, the authors noted that most women in the study who suffered an MS relapse either breastfed only briefly or did not breastfeed at all (Langer-Gould, et al., 2010). There was also a small sample group of 26 patients. Interestingly, the authors suggested that other hallmarks of lactation and pregnancy may strongly influence the link between vitamin D and MS disease severity (Langer-Gould, et al., 2010).

Vitamin D effects on pregnancy and breastfeeding hormones

As mentioned earlier, there are conflicting reports on how vitamin D levels change in breastfeeding women compared to during pregnancy. Vitamin D has been shown to reduce oestrogen levels via the production of aromatase, which converts testosterone to oestrogen (Dupuis et al., 2021), meaning that vitamin D may contribute in some small way to the oestrogen reduction after giving birth (Figure 2). This further points towards the possibility that vitamin D could increase during breastfeeding. There may be an inverse correlation between vitamin D and oestrogen levels. If this were the case, the neuroprotective effects of oestrogen reported by (Kunkl, M. et al., 2020) are likely replicated by vitamin D post-partum. This would go some way towards explaining the protection against MS relapses seen in breastfeeding women.

Vitamin D has also been shown to have similar physiological functions as the neuro-protective hormone, progesterone (Monastra et al., 2018). In addition, vitamin D works together with progesterone to promote regulatory T cell activity (Monastra et al., 2018). A synergistic relationship between vitamin D and oestrogen has been found in other studies (e.g., metabolic syndrome) (Huang et al., 2019). In light of this, the synergetic relationship between vitamin D and oestrogen/progesterone could be used to explain the reduction in MS relapses during pregnancy. However, oestrogen and progesterone levels drop post-partum, meaning that it is unlikely they would have much impact on MS relapses in breastfeeding women. It is possible that vitamin D could have similar neuroprotective effects as progesterone during breastfeeding, potentially in combination with other factor(s).

As shown in Figure 2, oxytocin and prolactin increase during breastfeeding. Whereas prolactin is pro-inflammatory, oxytocin is anti-inflammatory (Rasmi et al. 2023) (Türkoğlu et al. 2016). Tellingly, there is evidence that vitamin D prevents prolactin from rising to excessive levels during pregnancy (Krysiak et al., 2015). There is also evidence that vitamin D directly controls and increases oxytocin secretion via the stimulation of POMC neurons. As mentioned earlier, oxytocin is anti-neuroinflammatory and could prevent MS relapse (Friuli et al., 2021). Meanwhile, animal studies have found that vitamin D3-induced resistance to autoimmune encephalomyelitis is controlled by oestrogen (Nashold et al., 2009). A similar relationship may exist between vitamin D and oestrogen levels and multiple sclerosis disease severity. Oxytocin and vitamin D could work in combination to reduce the rate of MS relapses in breastfeeding women.

Vitamin D supplementation in MS patients

The influence of vitamin D on autoimmunity is thought to be sex-specific (Athanassiou et al., 2023), with the protective role of vitamin D in autoimmune disorders being stronger in women than in men (Dupuis et al., 2021). Vitamin D insufficiency in women of childbearing age (when MS is most likely to develop) has been reported to be between 38.5% and 69.3% (Aparecida da Silveira et al., 2022). Since vitamin D rises during pregnancy, and could potentially rise during breastfeeding, this presents more evidence that vitamin D could have a role in protecting against MS relapses in breastfeeding women.
Whereas research has already shown that vitamin D supplementation might benefit MS patients (Sintzel, Rametta and Reder, 2017), some patients have been found to be resistant to vitamin D supplementation (Athanassiou, L. et al., 2023). This would mean that the degree of vitamin D supplementation should be personalised to each patient (a precision medicine approach). This would also explain why vitamin D supplementation might not have worked in all MS patients in the past (Athanassiou, L. et al., 2023).

Conclusion

In conclusion, we propose that vitamin D rises during breastfeeding and thus alleviates MS disease severity and rate of relapse, possibly in combination with oxytocin, in a similar manner to oestrogen and progesterone during pregnancy (Figure 4). Future research could investigate this hypothesis.

Figure 4. Vitamin D and oxytocin could work in combination to reduce the risk of MS relapse in breastfeeding patients.