Cycling and early pregnant endometrium as a site of regulated expression of the Vitamin D system

P Vigano [1], D Lattuada [1], S Mangioni [1], L Ermellino [2], M Vignali [3], E Caporizzo [4], P Panina [4], M Besozzi [2], AM Di Blasio [2]

[1] Dept of Obstetrics, Gynaecology and Neonatology, Fondazione Policlinico-Mangiagalli-Regina Elena Hospital, University of Milano, Milano, Italy
[2] Pathology Laboratory and Molecular Biology Laboratory, Istituto Auxologico Italiano, Milano, Italy
[3] Dept of Obstetrics and Gynecology, Clinica “Macedonio Melloni”, University of Milano, Milano, Italy
[4] BioXell SpA, Milano, Italy

Vitamin D is a major regulator of calcium and phosphate homeostasis but its most potent metabolite has been demonstrated to affect a wide range of functions including anti-proliferative and immunomodulatory effects, suggesting a much broader physiologicical impact of the hormone in the body than originally envisioned.

In the late 1980s and 1990s, a particular attention was directed towards the potential significance of the vitamin D endocrine system in human reproductive processes. Increased blood levels of vitamin D were observed during oestroprogestins treatment as well as during human gestation. Uterine and placental cells were shown to synthetize vitamin D and a single report has demonstrated elevated serum levels of the hormone in patients with endometriosis. In recent years, interest in this specific topic has been increased because some genes regulated at the site of implantation are vitamin D-dependent.

Vitamin D is also a natural regulator of the immune system since it promotes the shift away from Th1-type responses and favour a Th2-type immunity by inhibiting the secretion of Th1 cytokines produced by T cells, macrophages and dendritic cells.

This study has investigated the significance of local production of vitamin D in the human uterus by evaluating the vitamin D system at endometrial and decidual level and in the ectopic endometrial tissue as well to verify any potential dysfunction of the system in endometriosis.

Endometrial cells and first trimester decidual cells have shown to express the enzyme 1alpha-OHase that converts the vitamin D precursor into the active form. The enzyme was also shown to be functionally active in converting the precursor into the active form of the hormone thus indicating that cycling endometrium may be included among the extrarenal sites able to synthesize vitamin D.

However, the expression of the enzyme was up-regulated in first trimester deciduas supporting the possibility that the hormone might be involved in some mechanisms of pregnancy. Indeed, the enzyme was subjected to the regulation of some inflammatory molecules that are crucial for the establishment of pregnancy.

Finally, both eutopic and ectopic endometrium of women with endometriosis express the enzyme with an increases expression in proliferative phase samples when compared to samples from control women. As for many other molecules found to be aberrantly present in endometriosis, it is difficult to clarify whether the increased endometrial 1alpha-OHase levels in proliferative phase represent a primary event or a consequence of the disease.

It might be hypothesized that a secondary endometrial response to the peritoneal inflammatory reactions, immediately following menstruation, is responsible for this increase. Alternatively, endometrium from women affected might be constitutively more able to produce vitamin D. In both cases, the hormone, mostly for its ability to modulate cytokine production and inflammatory mediators, may contribute to influence the functional activities of the immune populations in both the endometrial and peritoneal environments.

The vitamin D receptor, that is necessary for local vitamin D action, has been shown to be expressed in endometrial cells. The functional significance of active vitamin D production and the presence of vitamin D receptor were tested by evaluating expression of the target gene osteopontin. Osteopontin is a major constituent of the uterine-placental microenvironment with influence as a component of the endometrial gland secretion and as a gene product expressed by uterine stroma contributing to a decidualization-like transformation that correlates with the degree of conceptus invasiveness.

While vitamin D has been shown to induce the gene in some tissues, this is the first demonstration of the hormone-mediated stimulatory effect in endometrial and decidual cells giving further support for a role of vitamin D as a local paracrine signal.

The results of this study support the following observations:

1. Human cycling endometrium may be included among those sites able of extrarenal synthesis and action of vitamin D
   
   
2. The enzyme 1alpha-OHase is expressed in human endometrial stromal cells independently from the phase of the menstrual cycle but its expression is up-regulated in early pregnant versus cycling endometrium
   
   
3. The inflammatory cytokine IL-1beta is a potent inducer of endometrial 1alpha-OHase expression
   
   
4. Endometrium also expresses the vitamin D receptor
   
   
5. The osteopontin gene is a target of vitamin D action in both cycling and early pregnant endometrium
   
   
6. In endometriosis patients, the gene coding for 1alpha-OHase is expressed also in ectopic
   endometrium and its expression is enhanced in eutopic endometrium during the proliferative phase.
   

Taken together, these results confirm the necessity to further investigate the functional role of the vitamin D system at endometrial level.

Vigano P, Lattuada D, Mangioni S, Ermellino L, Vignali M, Caporizzo E, Panina-Bordignon P, Besozzi M, Di Blasio AM. Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system. J Mol Endocrinol 2006;36(3):415-24.