Vitamin D: how can it help manage my Endometriosis?

Posted By Braverman IVF & Reproductive Immunology || 6-Jan-2017

Many advertisements in the media are promoting the use of vitamin D and are encouraging you to determine if you are deficient for Vitamin D.
“Sign of low vitamin D. Do you take vitamin D supplement? 7 Surprising benefits of vitamin D” and the list goes on…
While an accumulation of scientific evidences describe the effects of vitamin D in cancer prevention, its potential role in endometriosis development is only recently emerging and display some conflicting results.
In this blog, we will give you a clear insight of what is known about Endometriosis in relation to Vitamin D and how it can help you manage your condition.

  1. Endometriosis

Endometriosis is a benign gynecologic disorder characterized by the presence of endometrial cells outside the endometrium (tissue normally lining the uterus) and affecting 10% of women of childbearing age and 40% of infertile women in the USA (1).
These endometrial cells can migrate and grow on other organs or structures of the body (ovaries, bladder, peritoneal cavity etc.)
Endometriosis is an inflammatory condition, driven by the hormone estrogen and may cause chronic pelvic pain, alteration of the menstrual cycle and sub/infertility.
It is important to highlight that many patients with endometriosis don’t present any symptoms (Silent endometriosis).
For more information, please consult our blog on the topic.

The causes leading to Endometriosis are multiple and include:

  • Genetic: women with a close relative affected by endometriosis have a higher risk of developing the disease.
  • Retrograde menstruation theory: the endometrial cells migrating outside the womb are coming from menses (although retrograde menstruation is very common among women)
  • Immunologic factors: many pro-inflammatory cytokines such as IFN-γ, IL-18 and IL-17 have been linked to the risk of developing endometriosis. Further, the prevalence of endometriosis is higher in patients affected by autoimmune diseases (inflammatory conditions).
  1. Vitamin D: synthesis and functions
  1. What is vitamin D?

Vitamin D is a fat-soluble vitamin belonging to the steroid hormone family.

Two main forms are essentials:

  • Vitamin D2 (ergocalciferol) that you can get through your diet.
  • Vitamin D3 (cholecalciferol) that you synthetize after sun exposure and represent 95% of your vitamin D production (2).

As shown in the Figure 1 below, these precursors bind to a binding protein (VDBP) to transit in the blood and reach the liver where they are modified into calcidiol (25-OH cholecalciferol) then metabolized a second time by the kidney to generate calcitriol (or 1, 25 dihydroxycholecalciferol), the active form of vitamin D.

From Kristin et al, Nature, 2007.

Figure 1: Vitamin D metabolic pathway.

  1. Role of vitamin D

By binding to its receptor (VDR), calcitriol (active form of vitamin D) regulates over 900 genes in human including several actions in reproductive tissues besides playing a key role in:

  • Calcium homeostasis
  • Regulation of cellular growth
  • Regulation of cellular differentiation
  • Regulation of immune response
  • Regulation of apoptosis (cell death)

Vitamin D and its receptor are present in the ovaries (3) where they stimulate the production of the steroid hormones estrogen and progesterone (4). The endometrium (uterus) itself can synthesize the active form of Vitamin D (5) and express the vitamin D receptor VDR as well (3).

  1. Vitamin D and Endometriosis
  • Serum Vitamin D levels: Conflicting results

A study led in women with endometriosis (proven by laparoscopy) showed that ENDO patients (n=87) have higher levels of the non-active form of vitamin D (calcidiol) when compared to controls women (disease-free patients, n=53).
The non-active form of vitamin D is the best indicator of vitamin D status because of its easy measurement and long half-life in circulation (~2–3 weeks) (6).
The difference seen between the two groups (ENDO vs. disease free patients) although significant (p=.05) was very small with a concentration of 24.9 ng/mL for ENDO patients versus 20.4 ng/mL for controls (7).
This difference is not seen when considering the active form of vitamin D (calcitriol).
A vitamin D deficiency has been defined as calcidiol levels between 20 and 37 ng/ml (8). In the present study, the cut-off value (28.2 ng/ml) defining high vitamin D levels falls within this range which means that even some ENDO patients characterized by high vitamin D levels in the study have in fact low vitamin D levels when considering this standard range.
Further, the number of patients is limited, altogether these data should be taken with caution to conclude any association of endometriosis with high Vitamin D levels.
Another study including women with ENDO (n=46) and healthy control patients (n=33) (9) showed no difference in Vitamin D levels between the two groups (25.7 ng/ml in ENDO patients vs 22.6 ng/ml in the disease free women). The number of patients was limited in both groups.
More recently, a study comparing n=1385 cases of ENDO proven by laparoscopy to over 69 000 disease-free women (The Nurse Health Study) showed that women in the highest quintile for vitamin D have 24% lower risk of endometriosis than those in the lower quintile (10). These results, without proving any causality between vitamin D levels and endometriosis, showed a strong association between low levels of Vitamin D and the occurrence of endometriosis.

  1. Vitamin D receptors (VDR) and Endometriosis
  • VDR expression levels in the endometrium

Higher expression of VDR levels in the endometrium were found in ENDO patients as compared to disease-free patients (9, 11).
Interestingly, a genetic study showed that specific forms of the genes coding for VDR (genetic variant) are strongly associated with endometriosis.
Indeed, the AT haplotype for VDR Bsml rs 1544410 and Fok1 rs 2228570 minor alleles showed strong association with endometriosis and may constitute a genetic risk factor (12).
Further, Fok1 give rise to two forms of VDR, the long form encoded by the minor allele is almost twice less efficient than the shorter form (13) which could mean that patients carrying this allele have lower VDR activity despite having normal VDR expression. Although encouraging, these results should be taken with caution and the same kind of studies should be run on larger groups of women of multiple ethnicities.

For now, and until the completion of larger studies including women of multiple ethnicities, it is not possible to affirm that the presence of these alleles are markers of a defective VDR and could cause endometriosis.
Although, there is currently no test available to ascertain VDR activity, it may be possible to indirectly evaluate it by measuring, on endometrial biopsy, the expression levels of specific vitamin D target genes such as HOXA10 (whose function is described below).
If Vitamin D levels within normal range failed to induce the expression of specific genes in the uterus, it may be due to a lack of VDR activity or a defective signal transduction. In which case, supplementing further with Vitamin D would be useless.

  1. Modulating Vitamin D pathway could limit Endometriosis development

Inflammation, Immune response, angiogenesis and apoptosis (cell death) are altered in favor of the survival and growth of the endometriotic tissue and are likely to enhance their adhesions outside the uterus (14).

Many studies showed that Vitamin D by regulating these parameters could play a beneficial role in limiting endometriosis development.

a-Vitamin D has a direct effect on immune regulation:

The activation of the vitamin D pathway has multiple effects on the immune function leading to less inflammation:

  • Inhibition of Th1 cells development (15)
  • Inhibition of Th-1 like cytokine secretion (16)
  • Dendritic cells and monocyte-macrophages become tolerogenic (differentiation of myeloid precursor to macrophages and inhibition of IFN-γ stimulated macrophages (17)
  • Inhibition of a master regulator of gene expression (NFKB) which leads to the suppression of chemokine production by cells in the organ targeted for inflammation (18).
  • Vitamin D have anti-angiogenic properties in a rat model for endometriosis

In a rat model of endometriosis (where endometriotic lesions could be simply induced after implantation of endometrial tissue), treatment with vitamin D before or during induction of the disease significantly reduces the size of the endometriotic lesions in addition to significantly reduce:
- a key factor promoting angiogenesis, VEGF (vascular endothelial growth factor)
- a molecule involved in the adhesion process, MMP-9 (matrix metalloproteinase 9).

Jointly, the inhibitor of MMP-9, namely TIMP-2 is significantly increased by Vitamin D treatment which limits the adhesion of endometrial tissue in the peritoneal cavity (19).

  • VDR agonist (elocalcitol) can prevent endometriotic lesions formation and reduces pre-existing lesions in a mice model for endometriosis

In a mice model for endometriosis (20), vitamin D administration during the induction of endometriosis represses lesions development by 42%.
If the administration is given before and maintained after the endometriosis induction, there is a 73% reduction in lesion development showing the preventing action of vitamin D.
Vitamin D, even given post endometriosis induction, can limit the disease progression, with 39% reduction in the development of lesions, highlighting its therapeutic efficacy to treat already established lesions.

Similarly, to the study in rat (19), vitamin D was here shown to repress the adhesions of endometrial cells in the peritoneal cavity. Further it prevents the recruitment of macrophages thus leading to a reduction of peritoneal inflammation.

  • Vitamin D and apoptosis in relation to endometriosis

Reduction of apoptosis (cell death) in unaffected tissue of women with endometriosis has been associated with susceptibility to develop lesions (21).

Among the regulators of apoptosis, survivin (an anti-apoptotic factor) is increased in endometriotic lesions while it is normally suppressed by Vitamin D (22).
In ENDO patients, low levels of Vitamin D could prevent or at least minimize survivin inhibition which could help endometriotic lesions from escaping apoptosis.

  1. Vitamin D and pregnancy

Many other evidences support the beneficial role of vitamin D in promoting women reproductive health and fertility.
Studies in animal (24) and in human (25) have shown that Vitamin D is a potent regulator of a process named decidualization that corresponds to the preparation of your uterus (with modification of endometrial cells) for the establishment of a pregnancy.
Vitamin D is a main regulator of a gene named HOXA10, essential for the regulation of the endometrial development and receptivity during the window of implantation (26). Lower expression of HOXA10 was found in the endometrium of ENDO patients (27) and could be due to lower vitamin D levels thus playing a role in ENDO patient’s infertility.

At Braverman Reproductive Immunology, we are constantly working in studying the latest discoveries in the field of reproductive immunology and promoting their use to offer you better diagnostic, monitoring and treatments.
We are systematically determining your Vitamin D levels and if appropriate, we recommend supplementation to replenish your vitamin D reserve and optimize your chances of having a healthy pregnancy.

References

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