While vitamin D has long been known to be important to innate and adaptive immune response, recent research has revealed a direct relationship between progesterone and vitamin D in influencing immune system function. The binding of active vitamin D (calcitriol) to the vitamin D receptor (VDR) mediates the effects of calcitriol on physiologic function, including mineral metabolism and immune response. Within the adaptive immune system, calcitriol plays a role in immune regulation via the VDR receptor on T cells, specifically by inducing regulatory T cells and suppressing effector T cells. Regulatory T cells are crucial to healthy immune function as they maintain tolerance to self.
In a 2015 study published in The Journal of Immunology, progesterone was shown to increase VDRs in T cells, thus increasing the T cells’ sensitivity to the influence of calcitriol. This increased sensitivity, in turn, upregulates the production of regulatory T cells. The results of this study are significant both for understanding the immune system shift during pregnancy and for understanding how optimal progesterone levels may help support healthy immune function and decrease autoimmunity among patients.
In order to carry a pregnancy, the body must show tolerance toward the fetus, which would otherwise be rejected as non-self. While this is achieved via multiple mechanisms, the suppression of effector T cells producing inflammatory cytokines such as IFNγ and IL-17 is contributory. In previous studies, progesterone has been shown to directly suppress production of these effector T cells at concentrations reached during pregnancy. Given the high number of progesterone receptors expressed in uterine tissues, this occurs most specifically in the uterus, though the elevated concentrations of progesterone during pregnancy reduces inflammatory cytokines outside of the uterus as well. This direct suppression, in combination with progesterone’s induction of VDRs, demonstrates the synergistic relationship between calcitriol and progesterone in reducing inflammation.
There are many potential implications of this synergistic relationship for both pregnant and non-pregnant individuals, some of which are discussed in a follow-up review article, also from 2015. Vitamin D deficiency is common among both the general population and pregnant individuals, and the upregulation of VDRs by progesterone may allow adequate regulatory T cells to develop in the setting of low calcitriol. In the central nervous system, both calcitriol and progesterone have been shown to be neuroprotective via anti-inflammatory mechanisms, and evidence suggests that the neuroprotective effect of progesterone is dependent on adequate calcitriol availability. Lastly, in a departure from the immune system, both progesterone and calcitriol are important for bone health and may also work in a synergistic manner in the growth and maintenance of bone.
While no direct clinical recommendations can be drawn from this study, it does further the understanding of the complex relationship between hormones and the immune system, and provides another argument for maintaining optimal vitamin D and progesterone levels.
Curious about your patient’s progesterone levels? Progesterone can be tested as a single marker or in combination with estradiol to obtain the clinically helpful Pg/E2 ratio. Furthermore, the Comprehensive and Comprehensive Plus hormone profiles provide progesterone levels, in addition to estrogen(s), androgens and adrenal hormones.