Hum. Reprod. Advance Access originally published online on June 4, 2007
Human Reproduction 2007 22(8):2273-2278; doi:10.1093/humrep/dem142
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Vitamin D reserve is higher in women with endometriosis
1 Infertility Unit, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via M. Fanti 6, 20122 Milano, Italy 2 BioXell S.p.A., Milan, Italy 3 Istituto Auxologico Italiano, Milan, Italy 4 Università degli Studi di Milano, Milan, Italy
5 Correspondence address. Tel: +39-02-57992583; Fax: +39-02-50320260; E-mail: dadosomigliana{at}yahoo.it
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Abstract |
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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.
Key words: endometriosis/vitamin D/calcium
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Introduction |
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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 1
-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-
(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, 1-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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Materials and Methods |
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Between October 2004 and December 2005, all women of reproductive age who were referred to the Gynecological Surgical Service of the Departments of Obstetrics and Gynecology of the "Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena" were evaluated prior to surgery for eligibility. Patients reporting malignancy, hypertension, diabetes and coronary, hepatic or renal diseases were excluded. Other exclusion criteria were pregnancy, menopause, hormonal treatment (including oral contraceptive) during the past three months and medications known to affect bone metabolism. Patients who were previously operated on for endometriosis and who were found to be disease-free at the time of surgery were excluded. The protocol of the study was approved by the local Ethical Committee and all recruited patients gave written informed consent.
Peripheral venous blood samples were obtained from the patients after an overnight fast immediately before laparoscopy and centrifuged at 700 g at 4°C for 10 min. The resulting sera were frozen at –20°C until assayed. The quantitative detection of 25-hydroxyvitamin-D3 levels was performed using a commercially available kit based on a chemiluminescence technology (DiaSorin, Inc. Corp., Stillwater, MN, USA). The intraassay and interassay coefficient of variations (CVs) were 10 and 15%, respectively. Serum 1,25-dihydroxyvitamin-D3 was measured by radioimmunoassay using a kit (DiaSorin, Inc. Corp., Stillwater, MN, USA). The intraassay and interassay CVs were 4 and 7%, respectively. Serum calcium was measured colorimetrically using a standardized routine procedure.
Endometriosis was staged according to the revised American Society for Reproductive Medicine (ASRM) classification (rASRM, 1997). All interventions were performed under the supervision of surgeons engaged in the field of reproductive surgery for at least 10 years.
Data are reported as Mean ± SD and were analyzed using Fisher exact test, Student’s t-test, analysis of variance (ANOVA) and least significant difference (LSD) post-hoc test as appropriate (Statistical Package for the Social Sciences /Windows 14.0, Chicago, IL, USA). P 
0.05 was considered statistically significant.
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Results |
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Overall, 140 consecutive patients undergoing surgery satisfied the selection criteria. Endometriosis was documented in 87 cases (62%) while the remainder (n = 53, 38%) were free of visible lesions and were considered controls. According to the revised ASRM classification, endometriosis stage I–II was recorded in 13 cases, stage III in 39 cases and stage IV in 35 cases. The principal diagnoses of the control group were as follows: uterine fibroids (n = 13), sero-mucinous ovarian cysts (n = 12), unexplained infertility and/or pelvic pain (n = 12), pelvic inflammatory disease (PID, n = 7), paraovarian cysts (n = 6) and dermoid cysts (n = 3). Five women in the study group and none in the control group had undergone previous surgery for endometriosis. All the women were of Caucasian origin. Baseline clinical characteristics of cases and controls are shown in Table 1.
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Even if the sample size recruited in the present study does not allow us to draw definite conclusions regarding the mode of distribution of serum levels of 25-hydroxyvitamin-D3, 1,25-dihydroxyvitamin-D3 and Ca2+, the Skewness and Kurtosis indexes were compatible with a normal distribution: indeed, the Skewness index (± SE) and the Kurtosis index (±SE) for the three molecules were 1.44 ± 0.20 and 2.24 ± 0.41, 0.74 ± 0.20 and 0.35 ± 0.41 and 0.19 ± 0.21 and 0.24 ± 0.41, respectively. Parametric statistics were thus employed.
Serum levels of 25-hydroxyvitamin-D3, 1,25-dihydroxyvitamin-D3 and Ca2+ in women with and without endometriosis are shown in Fig. 1. A statistically significant difference emerged for 25-hydroxyvitamin-D3. Mean levels of the molecule in affected women and controls were 24.9 ± 14.8 and 20.4 ± 11.8 ng/ml, respectively (P = 0.05) The concentration of 1,25-dihydroxyvitamin-D3 and Ca2+ did not significantly differ in the two groups. Serum levels of 1,25-dihydroxyvitamin-D3 in women with and without endometriosis were 52.7 ± 17.6 and 48.9 ± 17.5 ng/ml, respectively (P = 0.22) whereas those of Ca2+ were 9.3 ± 0.4 and 9.4 ± 0.4 mg/dl, respectively (P = 0.16). In order to rule out a confounding effect of some of the diagnostic groups included in the controls, serum levels of 25-hydroxyvitamin-D3, 1,25-dihydroxyvitamin-D3 and Ca2+ were also evaluated according to the specific diagnoses of the controls. And this analysis did not show any statistical significance (P = 0.50, P = 0.76 and P = 0.49, respectively). 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). Conversely, levels of the three molecules did not vary according to the cycle phase (P = 0.92, 0.44 and P = 0.64, respectively).
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Serum concentration of 25-hydroxyvitamin-D3, 1,25-dihydroxyvitamin-D3 and Ca2+ was also evaluated according to the severity of endometriosis using ANOVA test (Table 2). Post-hoc LSD tests revealed statistically significant differences for 25-hydroxyvitamin-D3 when comparing controls to endometriosis stage IV (P = 0.03). Although statistically significant, an increase in serum levels of 1,25-dihydroxyvitamin-D3 with the severity of the disease was also observed.
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Levels of 25-hydroxyvitamin-D3, 1,25-dihydroxyvitamin-D3 and Ca2+ in women with and without endometriosis were also evaluated in a dichotomous manner. To this end, the 75th percentile of the entire cohort distribution for the three molecules was used as a discriminating cut-off value. Results from this analysis are shown in Table 3. The most interesting result was observed for 25-hydroxyvitamin-D3 serum concentration. Levels were above the 75th percentile in 29 cases (33%) and 5 controls (9%) (P = 0.001). The odds ratio (OR) (95% Confidence Interval(CI)) for endometriosis in women with serum levels of 25-hydroxyvitamin-D3 exceeding 28.2 ng/ml was 4.8 (1.7–13.4). Diagnoses of the five control cases whose serum levels were above the cut-off value were as follows: myoma (1 case), sero-mucinous cyst (2 cases), PID (1 case) and dermoid case (1 case).
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Discussion |
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In the present study, we have observed that levels of 25-hydroxyvitamin-D3 were significantly increased in the sera of women with endometriosis. A biological gradient showing more striking differences in patients with advanced stages was also noted, thus providing additional support to the biological relevance of the observed association. Of particular relevance is that a marked increase in risk of endometriosis was detected in the group of women with serum levels of 25-hydroxyvitamin-D3 exceeding the 75th percentile. Conversely, serum concentrations of 1,25-dihydroxyvitamin-D3 and Ca2+ did not significantly differ in women with and without the disease.
Failure to demonstrate markedly higher levels of 1,25-dihydroxyvitamin-D3 and Ca2+ was somewhat expected. Indeed, in women with endometriosis, clinical evidence of excessive levels of vitamin D such as hypercalcemia had never been previously reported. Hypercalcemia has been described in patients with a number of granulomatous diseases which are the best known examples of overproduction of active vitamin D. In these disorders, activated macrophages vigorously synthesize 1,25-dihydroxyvitamin-D3 which spills over into the general circulation in large enough quantities to elicit hypercalcemia (Sharma, 2000). Unregulated 1,25-dihydroxyvitamin-D3 production is also a described mechanism for hypercalcemia in patients with Hodgkin’s and non-Hodgkin’s lymphoma (Hewison et al., 2003). In these conditions, macrophages adjacent to the tumor are the most likely source of the vitamin D hormone (Hewison et al., 2003). Even if endometriosis is regarded as an inflammatory condition, the inflammatory process is generally less extensive than the one associated with granulomatous diseases or lymphomas. As a consequence, it is not surprising that serum levels of 1,25-dihydroxyvitamin-D3 and Ca2+ are not markedly altered in affected women. Of note, however, we have observed a slightly higher serum concentration of 1,25-dihydroxyvitamin-D3 in women with endometriosis, particularly for the advanced stages, but, in contrast to the results reported by Hartwell et al. (1990), this difference did not reach statistical significance.
Conversely, serum concentration of 25-hydroxyvitamin-D3 was significantly increased in women with the disease. More importantly, women with serum levels of 25-hydroxyvitamin-D3 exceeding the 75th percentile (28.2 ng/ml) were shown to have an almost 5-fold increased risk of being affected. Hartwell et al. (1990) did not document significant differences in serum levels of 25-hydroxyvitamin-D3 but the sample size of this study was considerably smaller and a type II error cannot be excluded. Moreover, these authors did not perform an analysis using a threshold value (Hartwell et al., 1990). We speculate that the increase in serum concentration of 25-hydroxyvitamin-D3, which is the best indicator of vitamin D availability, might represent a possible risk factor for endometriosis. According to the hypothesis surrounding the present study, 25-hydroxyvitamin-D3 would represent an important substrate that can be used by cells within the peritoneal cavity to bring about local immune suppression and thus to permit the development of endometriosis. Of relevance here is that endometrial cells express 1-hydroxylase and they can thus directly convert 25-hydroxyvitamin-D3 into its active form 1,25-dihydroxyvitamin-D3 (Vigano et al., 2006b). Expression of 1-hydroxylase is enhanced in the endometrium of women with endometriosis and it may be speculated that this property may facilitate the implantation of these cells in the peritoneal cavity by creating a local favorable immune milieu. This phenomenon may be subsequently further amplified during the development of local inflammation since macrophages and lymphocytes can also convert 25-hydroxyvitamin-D3 into its active form (Lehman, 2005).
From an epidemiological point of view, two major points have to be considered in interpreting our results. Firstly, our study design does not allow us to definitively establish causal relationships between vitamin D reserve and endometriosis development. It cannot be excluded that confounding factors may play a role. Until more evidence becomes available, these results have thus to be interpreted only in terms of an association. Secondly, even if a causative role does exist, it cannot be clarified whether higher levels of 25-hydroxyvitamin-D3 increase the risk of endometriosis, or, conversely, if lower levels of vitamin D represent a protective factor. In this regard, it has to be noted that serum levels of 25-hydroxyvitamin-D3 in our cohort were generally low. Even if there is no consensus on the optimal serum concentration of 25-hydroxyvitamin-D3, threshold values that have been suggested to define deficiency vary between 20 and 37 ng/ml (Bandeira et al., 2006). The 75th percentile calculated in the present study and used as a cut-off value (28.2 ng/ml) falls within this range. On this basis, we cannot exclude the possibility that lower levels 25-hydroxyvitamin-D3 represents a protective factor.
Even if the causes surrounding the higher levels of 25-hydroxyvitamin-D3 in the sera of women with endometriosis were not specifically evaluated in the present study, some hypotheses may be drawn. A number of personal and environmental factors influence systemic levels of 25-hydroxyvitamin-D3: dietary vitamin D intake, age, season, race, latitude, skin pigmentation, drugs, local state of the atmosphere and individual behavior (Webb, 2006).
Interestingly, an association between endometriosis and diet has recently been reported. A reduced risk of the disease emerged for a higher intake of green vegetables and fresh fruits whereas the risk is enhanced for a higher intake of ham, beef and other red meat (Parazzini et al., 2004). Even if these authors did not perform a specific evaluation of the dietary content of vitamin D, it may be speculated that dietary intake may play a role in explaining results observed in the present study. However, this hypothesis seems unlikely since, even if vitamin D requirements may also be achieved through diet, the relative contribution of dietary intake is believed to be slight (Cantorna et al., 2004). More than 90% of the vitamin D requirement for most people comes from exposure to sunlight (Holick, 2004). Indeed, assimilation of vitamin D through diet is problematic because only a few foods are naturally rich in this vitamin (Cantorna et al., 2004).
As a consequence, the higher levels of 25-hydroxyvitamin-D3 observed in women with endometriosis would originate from their own skin production. Interestingly, cross-sectional studies have suggested that the proportion of naturally red haired women is greater among women with endometriosis compared to the general population (Frish et al., 1992; Woodworth et al., 1995; Wyshak and Frish, 2000). A recent large cohort study has confirmed this finding (Missmer et al., 2006). The sharing of similar genetic and/or epidemiological factors has been advocated to interpret these data. With regard to the results observed in the present study, it may be speculated that fair-haired races are also fair-skinned and consequently their skin maximizes the use of any UV for vitamin D synthesis. The finding that African Americans have a reduced incidence of endometriosis compared to Caucasians is consistent with this interpretation (Missmer et al., 2004). In this regard, it is of interest to note that there is also some evidence suggesting a possible association between endometriosis and melanoma (Brinton et al., 2005; Somigliana et al., 2006), a cancer known to be triggered by UV exposure (Naldi et al., 2000).
The possible use of serum levels of 25-hydroxyvitamin-D3 as a new marker of endometriosis needs further investigation. Data from the present study does not clearly support this possibility. Indeed, using the cut-off value stated in our paper (28.2 ng/ml corresponding to the 75th percentile), the sensitivity and specificity were 33 and 91%, respectively. Even if the specificity is useful, the sensitivity appears to be insufficient. Moreover, a notable limit of the use of 25-hydroxyvitamin-D3 as a marker of the disease is that this molecule has remarkable seasonal variations and depends on recent exposure to sunlight. In order to evaluate a role as a screening marker, patients would have to be evaluated in codified conditions. The present study was thus not properly designed to address this issue.
In conclusion, this study suggests that perturbations to the vitamin D status are present in women with endometriosis, independent of season, age and therapy. Future studies are warranted to clarify whether the increased levels of 25-hydroxyvitamin-D3 play a causative role in endometriosis development or, alternatively, if they merely reflect confounding factors.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adorini L. Intervention in autoimmunity: the potential of vitamin D receptor agonists. Cell Immunol (2005) 233:115–124.[CrossRef][ISI][Medline]
Bandeira F, Griz L, Dreyer P, Eufrazino C, Bandeira C, Freese E. Vitamin D deficiency: a global perspective. Arq Bras Endocrinol Metab (2006) 50:640–646.[Medline]
Brinton LA, Westhoff CL, Scoccia B, Lamb EJ, Althuis MD, Mabie JE, Moghissi KS. Causes of infertility as predictors of subsequent cancer risk. Epidemiology (2005) 16:500–507.[CrossRef][ISI][Medline]
Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin-D3, and the immune system. Am J Clin Nutr (2004) 80(Suppl. 6):1717S–1720S.
De Luca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr (2004) 80(Suppl. 6):1689S–1696S.
Frisch RE, Wyshak G, Albert LS, Sober AJ. Dysplastic nevi, cutaneous melanoma, and gynecologic disorders. Int J Dermatol (1992) 31:331–335.[ISI][Medline]
Hartwell D, Rodbro P, Jensen K, Thomsen SB, Christinsen C. Vitamin D metabolites: relation to age, menopause and endometriosis. Scand J Clin Lab Invest (1990) 50:115–121.[ISI][Medline]
Hewison M, Kantorovich V, Liker HR, Van Herle AJ, Cohan P, Zehnder D, Adams JS. Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages. J Bone Miner Res (2003) 18:579–582.[CrossRef][ISI][Medline]
Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr (2004) 80(Suppl. 6):1678S–1688S.
Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril (2001) 75:1–10.[CrossRef][ISI][Medline]
Lehman B. The vitamin D3 pathway in human skin and its role for regulation of biological processes. Photochem Photobiol (2005) 81:1246–1251.[CrossRef][ISI][Medline]
Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM, Hunter DJ. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric and lifestyle factors. Am J Epidemiol (2004) 160:784–796.
Missmer SA, Spiegelman D, Hankinson SE, Malspeis S, Barbieri RL, Hunter DJ. Natural hair color and the incidence of endometriosis. Fertil Steril (2006) 85:866–870.[CrossRef][ISI][Medline]
Naldi L, Imberti LG, Parazzini F, Gallus S, La Vecchia C. Pigmentary traits, modalities of sun reaction, history of sunburns, and melanocytic nevi as risk factors for cutaneous malignant melanoma in the Italian population: results of a collaborative case-control study. Cancer (2000) 88:2703–2710.[CrossRef][ISI][Medline]
Parazzini F, Chiaffarino F, Surace M, Chatenoud L, Cipriani S, Chiantera V, Beni G, Fedele L. Selected food intake and risk of endometriosis. Hum Reprod (2004) 19:1755–1759.
rASRM. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril (1997) 67:817–821.[CrossRef][ISI][Medline]
Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med (2000) 6:442–447.[CrossRef][Medline]
Somigliana E, Vigano P, Parazzini F, Stoppelli S, Giambattista E, Vercellini P. Association between endometriosis and cancer: a comprehensive review and a critical analysis of clinical and epidemiological evidence. Gynecol Oncol (2006) 101:331–341.[CrossRef][ISI][Medline]
Van Etten E, Decallonne B, Verlinden L, Verstuyf A, Bouillon R, Mathieu C. Analogs of 1,25-dihydroxyvitamin D3 as pluripotent immunomodulators. J Cell Biochem (2003) 88:223–226.[CrossRef][ISI][Medline]
Vigano P, Somigliana E, Chiodo I, Abbiati A, Vercellini P. Molecular mechanisms and biological plausibility underlying the malignant transformation of endometriosis: a critical analysis. Hum Reprod Update (2006a) 12:77–89.
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 (2006b) 36:415–424.
Vignali M, Infantino M, Matrone R, Chiodo I, Somigliana E, Busacca M, Vigano P. Endometriosis: novel etiopathogenetic concepts and clinical perspectives. Fertil Steril (2002) 78:665–678.[CrossRef][ISI][Medline]
Webb AR. Who, what, where and when- influences on cutaneous vitamin D synthesis. Prog Biophys Mol Biol (2006) 92:17–25.[CrossRef][ISI][Medline]
Woodworth SH, Singh M, Yussman MA, Sanfilippo JS, Cook CL, Lincoln SR. A prospective study on the association between red hair color and endometriosis in infertile patients. Fertil Steril (1995) 64:651–652.[ISI][Medline]
Wyshak G, Frisch RE. Red hair color, melanoma, and endometriosis: suggestive associations. Int J Dermatol (2000) 39:798.[ISI][Medline]
Submitted on January 30, 2007; resubmitted on April 23, 2007; accepted on May 1, 2007.
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