Vitamin D Reserve is Higher in Women with Endometriosis

Edgardo Somigliana; Paola Panina-Bordignon; Simone Murone; Pietro Di Lucia; Paolo Vercellini; Paola Vigano

Disclosures

Hum Reprod. 2007;22(8):2273-2278. 

In This Article

Abstract and Introduction

Abstract

Background: An immune-mediated defect in recognition and elimination of endometrial fragments refluxed in the peritoneal cavity has been hypothesized to play a crucial role in endometriosis development. Since vitamin D is an effective modulator of the immune system, we have hypothesized that the vitamin D status may have a role in the pathogenesis of endometriosis.
Methods: Women of reproductive age selected for surgery for gynecological indications were enrolled in this prospective cohort study. Serum levels of 25-hydroxyvitamin-D3, 1,25-dihydroxyvitamin-D3 and Ca2+ were assessed.
Results: Eighty-seven women with endometriosis and 53 controls were recruited. Mean (± SD) levels of 25-hydroxyvitamin-D3 in women with and without endometriosis were 24.9 ± 14.8 ng/ml and 20.4 ± 11.8, respectively (P = 0.05). The Odds Ratio (95% Confidence Interval) for endometriosis in patients with levels exceeding the 75th percentile of the serum distribution of the molecule (28.2 ng/ml) was 4.8 (1.7-13.5). A positive gradient according to the severity of the disease was also documented. A trend towards higher levels of 1,25-dihydroxyvitamin-D3 and Ca2+ was observed in women with endometriosis, but differences did not reach statistical significance. As expected, serum concentrations of 25-hydroxyvitamin-D3 and 1,25-dihydroxyvitamin-D3, but not Ca2+, are influenced by the season (P < 0.001, P = 0.004, P = 0.57, respectively), while levels of the three molecules did not vary according to the phase of the menstrual cycle.
Conclusions: Endometriosis is associated with higher serum levels of vitamin D.

Introduction

The pivotal role of vitamin D in mineralizing the skeleton and in regulating plasma calcium concentration has been recognized for many decades (De Luca, 2004; Lehman, 2005). Even if dietary intake may contribute to the physiological requirement for vitamin D, for the most part it is produced in the skin through a robust photolytic process acting on 7-dehydrocholesterol, a derivate of cholesterol. The natural form of the vitamin D produced in the skin, named vitamin D3, is biologically inert. It is metabolized in the liver to 25-hydroxyvitamin-D3 and then in the kidney to its biologically active form 1,25-dihydroxyvitamin-D3, also named calcitriol. The 25-hydroxyvitamin-D3 is metabolically inactive but circulating levels of the molecule are of great clinical utility since they are commonly used to monitor vitamin D reserve (De Luca, 2004; Lehman, 2005).

In recent years, it has also emerged that the function of the vitamin D system is not limited to the regulation of plasma calcium concentration and skeleton mineralization. The vitamin plays an important role in several other physiological systems and, in particular, it has been shown to be an effective modulator of the immune system (Holick, 2004). Various cell types involved in immunologic reactions (monocytes, Langerhans cells, T and B lymphocytes) not only express vitamin D receptor but also possess 1α-hydroxylase, the enzyme that catalyzes the synthesis of the active form of vitamin D (Van Etten et al., 2003; Lehman, 2005). Under experimental conditions, 1,25-dihydroxyvitamin-D3 is strongly immunosuppressive and improves various T-helper-1 triggered diseases including autoimmune encephalomyelitis and autoimmune diabetes in mice and psoriasis in humans. Moreover, it strongly inhibits the function of natural killer cells and promotes T-helper-2 differentiation leading to a T-helper-2 phenotype with augmented production of interleukin(IL)-4, IL-5 and IL-10, and reduced synthesis of interferon-γ (Lehman, 2005). In general, it induces a phenotype that promotes tolerance and suppresses immunity after stimulation with antigen (Van Etten et al., 2003; Lehman, 2005). In line with these findings, epidemiological evidence supports a protective role of vitamin D against some autoimmune diseases that are characterized by a T-helper-1 immunity such as multiple sclerosis, rheumatoid arthritis and type I diabetes mellitus (Holick, 2004; Adorini, 2005).

In this study, we have hypothesized a possible relationship between endometriosis and the vitamin D system. Endometriosis has been shown to be associated with significant immune derangements. Lymphoid function appears to be altered and natural killer cell cytoxicity is hampered (Lebovic et al., 2001; Vigano et al., 2006a). Immune-stimulating drugs have been shown to effectively prevent and treat endometriosis in animal models (Vignali et al., 2002). Thus, the immune system has been advocated to play a critical role in the pathogenesis of the disease. The impaired immune-mediated clearance of endometrial fragments refluxed into the pelvic peritoneum during menstruation has been hypothesized to permit these cells to survive and implant in ectopic sites. The hypothesis tested in the present study is that the individual supply of vitamin D may influence the development of the disease by locally modulating the immune system within the peritoneal cavity.

The possible link between endometriosis and the vitamin D system has been poorly investigated in the past. The first observation was reported by Hartwell et al. (1990). These authors observed higher serum levels of 1,25-dihydroxyvitamin-D3 and similar levels of 25-hydroxyvitamin-D3 in a small group of women with endometriosis when compared to controls. This, however, remained the only observation for up to 15 years. Recently, our group has demonstrated that human endometrium can be included among those sites capable of extrarenal synthesis of active vitamin D (Vigano et al., 2006b). The enzyme that catalyzes the synthesis of 1,25-dihydroxyvitamin-D3, 1α-hydroxylase, is expressed in both eutopic and ectopic endometrium and its expression is enhanced in eutopic endometrium of women with endometriosis. Measurement of 1,25-dihydroxyvitamin-D3 levels in the supernatant of endometrial cells treated with 25-hydroxyvitamin-D3 confirmed that endometrium represents a site of local conversion from the precursor to the active form (Vigano et al., 2006b).

Overall, the relationship between endometriosis and the vitamin D endocrine system remains to be clarified. In order to gain insights into this topic, we have examined the status of serum vitamin D in a cohort of women with and without endometriosis confirmed at laparoscopy.

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