Clinics in Mother and Child Health

Designing a Pragmatic Dose-Escalation for Vitamin-D to Reduce Endometriosis Related Pain after Laparoscopy in Vitamin- D Deficient Women

Aml El-Shabrawy^* Faculty of Medicine, Department of Obstetrics and Gynecology, Ain Shams University, Cairo, Egypt
^*Correspondence: Dr. Aml El-Shabrawy, Faculty of Medicine, Department of Obstetrics and Gynecology, Ain Shams University, Cairo, Egypt, Email:

Received: 05-Aug-2021 Published: 26-Aug-2021, DOI: 10.35248/2090-7214.21.s8.002

Introduction

Vitamin-D status is related to sunlight acquaintance and hence be determined by latitude. Accordingly, vitamin-D deficiency, defined as a serum 25-hydroxy vitamin-D3 (25-OHD3) level < 12 ng/ml, is very common in Northern Europe this is primarily attributed to the lack of enough daylight exposure and low dietary vitamin-D.

Endometriosis is defined as evolution of endometrial glands and stroma outside the uterine cavity. It affects more than 10% of reproductive-age females [1,2]. Endometriosis is an established cause of infertility, pelvic discomfort, dysmenorrhea, and dyspareunia in reproductive-age women. Its diagnosis is by inspection of the pelvis during laparoscopy [1]. In women with pelvic pain and infertility, the incidence of endometriosis is as high as 90%. Pain and subfertility can seriously deteriorate quality of life in affected ladies [3,4].

Endometriosis simulates some autoimmune and neoplastic illnesses, including hereditary manifestations and immunological aberrations in B and T cells, augmented angiogenesis, invasion of endometrial cells to neighboring organs (e.g., bladder and intestine), and demand for repeat surgeries due to recurrence [1,5-7]. Numerous mechanisms for the cause and management of this disease are proposed and the managements are established on these uncertain mechanisms as progestin, GNRH agonists and antagonists [1].

Also, medications linked to fat metabolism (e.g., Simvastatin) can be administered in some cases [8,9]. It has been revealed that inflammatory mechanism is essential in the occurrence of the disease [10], so management must not be altered from that of other inflammatory illnesses [11]. Vitamin-D levels may be linked to many disorders as polycystic ovarian disease, endometriosis, breast and ovarian cancer, increased arterial stiffness in older patients, and myasthenia gravis [12-18]. It is proven now that vitamin-D plays many essential functions as listed.

• A role in normal cellular growth [19].

• Vitamin-D has immune regulatory effects in chronic infla mmatory responses [20].

• Vitamin-D increases anti-infla mmatory cytokines production and decreasespro inflammatorycytokines [19-24].

• Vitamin-D induces apopto sis and suppression of angiogenesis in and in [25-28].

Though an unforeseen correlation between vitamin-D and endometriosis has been described in numerous studies, but the published randomized clinical trial on endometriosis and vitamin-D treatment in females are still very few. We revealed the relationship between vitamin-D and endometriosis in a double-blind, randomized clinical trial concentrating at the effect of vitamin-D supplementation on alleviation of pain after laparoscopic diagnosis and management.

Patients and Methods

This randomized, double-blind clinical trial was accomplished in a single tertiary hospital from Jan 2018 to Dec 2020. A total of 50 patients with established vitamin-D deficiency (serum 25- OHD3 level <12 ng/ml) were included.To find patients with endometriosis, laparoscopy was done for numerous symptoms, as ovarian cyst, infertility, pelvic pain, and dysmenorrhea.

This randomized, double-blind clinical trial was accomplished in a single tertiary hospital from Jan 2018 to Dec 2020. A total of 50 patients with established vitamin-D deficiency (serum 25- OHD3 level <12 ng/ml) were included.To find patients with endometriosis, laparoscopy was done for numerous symptoms, as ovarian cyst, infertility, pelvic pain, and dysmenorrhea.

In the patients with endometriosis in the second menses after laparoscopic diagnosis and treatment, the VAS test was repeated. Inclusion and exclusion criteria are mentioned in Table 1.

Table 1: Inclusion and exclusion criteria.

After authorization by the Hospital Ethics Committee, eligible patients were assigned by simple randomization to receive either vitamin-D or placebo. In the vitamin-D group (D group), we prescribed oral vitamin-D 50 000 iu/weekly for 6 months and in the placebo group (P group) we prescribed 1 capsule of placebo weekly for 6 months. VAS test was repeated for the 2 groups. Statistical analysis: Retrieved data were recorded on an investigative report. The data were analyzed with SPSS® for Windows®, version 15.0 (SPSS, Inc, USA).

Results

In table 2, the mean age of participants in group I was 27.48±9.5 years and in group II was 26.84 ± 3.25. Causes of laparoscopy in women with endometriosis diagnosed by laparoscopy were dysmenorrhea (n=22 in group I and 22 in group II), ovarian cyst (n=4 in group I and 7 in group II), chronic pelvic pain (n=23 in group I and 21 in group II), and infertility (n=15 in group I and 17 in group II). In some patients, there was more than 1 reason for laparoscopy. Severity of endometriosis were nearly similar in both groups (P>0.05) (Table 2).

Table 2: Comparing group I (vitamin-D) group and group II (placebo group) as regarding the baseline characters and pain score before and after laparoscopy

Before laparoscopy, the mean pelvic pain score in the vitamin-D group was 3.76 ± 2 and 4.8 ± 2.25(p=0.0905) in the placebo group. Before laparoscopy, the mean dysmenorrhea pain score in the vitamin-D group was 4 ± 2.25 and in placebo group it was 4.52 ± 1.75 (p=0.3665). a comparison between the 2 groups for severity of pelvic pain and/or dysmenorrhea at different time points (before laparoscopy, in second menses after laparoscopy, and at 6 months after laparoscopy). At the second menses after laparoscopy, there was no significant difference between the 2 groups for pelvic pain (p=0.55) and dysmenorrhea (p=0.43), and at 6 months after laparoscopy there was no significant difference between mean pain scores in the 2 groups.

Mean pelvic pain at 6 months after laparoscopy in the vitamin-D group was 2.96 ± 2 and in placebo group it was 3.3±2 (p=0.55). Mean dysmenorrhea was 2.44±1.5 in the vitamin-D group and 2.5 ± 1.3 in the placebo group (p=0.88). Table 3 and 4 shows a comparison among the means before and after laparoscopy in group I and II respectively by one way analysis of vaiance (ANOVA) with no significant difference in pelvic pain score but the improvement in dysmenorrhea score (Tables 3 and 4).

Table 3: Comparing the means before and after laparoscopy in group I by one way analysis of vaiance (ANOVA).

Table 4: Comparing the means before and after laparoscopy in group II by one way analysis of vaiance (ANOVA).

Discussion

In this double-blind, randomized clinical trial, at 6 months after laparoscopic treatment of endometriosis there was no significant difference between effect of vitamin-D 3 (cholecalciferol) and placebo on severity of dysmenorrhea and/or pelvic pain. A study on vitamin-D receptor gene polymorphism in endometriosis compared 132 infertile women with endometriosis with 132 fertile women, reporting no significant difference and suggesting that vitamin-D receptor gene polymorphism does not play an important role in the pathogenesis of endometriosis [29].

In some studies, higher plasma levels of 1, 25-dihydroxy vitamin- D 3 and higher intake of dairy foods was associated with lower risk of endometriosis [30,31]. Conversely, another study compared serum vitamin-D levels of 87 women with endometriosis with 53 women without endometriosis; the mean serum levels of 1, 25-dihydroxy vitamin-D 3 in women with and without endometriosis were 24.9 ± 14.8 ng/ml and 20.4 ± 11.8, respectively (P=0.05) and the study concluded that endometriosis is associated with higher serum levels of vitamin- D [32]. A systematic review of 10 case-control studies and 1 cohort study on women’s diet found that women with endometriosis had lower consumption of vegetables and omega-3, and reported a significant association between diet and endometriosis [33].

Vitamin-D binding protein (DBP) is a plasma glycoprotein that modulates immune and inflammatory responses and also controls transport of vitamin-D metabolites and bone development [34]. In a study comparing 13 ectopic endometrial tissues and 6 normal endometrial tissues, vitamin-D binding protein was significantly higher in the ectopic endometrial tissues (P<0.05) [35]. A systematic review of research from 1946 to 2013 on vitamin-D and endometriosis reported that women with endometriosis had higher serum levels of vitamin-D binding protein [36]. Another study compared serum and peritoneal levels of DBP in 26 women with endometriosis and 17 women with other benign gynecological conditions and reported that women with endometriosis had higher serum levels of DBP than in the control group [37]. A study comparing urinary levels of DBP in 57 women with endometriosis with levels in 38 controls found that the urinary level of DBP was significantly higher in patients with endometriosis [38].

A study using a rat model of endometriosis reported that treatment with vitamin-D 3 produced fibrosis and apoptosis in the stroma of tissues with endometriosis [28]. A study on induced endometriosis in adult Balb female mice reported that administration of 100 μg/kg/day Elocalcitol (a vitamin-D receptor agonist) for 3 weeks reduced total lesion weight [39].

Because a relationship between vitamin-D and endometriosis has been suggested by multiple studies, and since there has been no randomized clinical trial on endometriosis and vitamin-D treatment in women, we decided to explore this relationship. In the present study on endometriosis-related pain, we found no significant difference in results of vitamin-D treatment vs. placebo at 24 weeks after surgical diagnosis and treatment [40-43].

Vitamin-D is a fat-soluble vitamin mainly produced in the body from food and supplements and cutaneous sun exposure. Vitamin-D deficiency is defined as serum 1.25-dihydroxy vitamin-D 3 levels under 20 ng/ml. Vitamin-D deficiencies are prevalent worldwide. In the USA, it is reported in 52% of black and Hispanic adolescents in Boston and in 48% of girls in Maine, and it is seen in 40–100% of elderly men and women in the USA and Europe [44]. A study in Germany found that 57% of people 18–79 years old were vitamin- D deficient [45]. The prevalence of vitamin-D deficiency was reported to be 90% in healthy subjects in Delhi, India [46]. In a systematic review of 195 studies in 44 countries found that 37.3% of studies found that the mean serum vitamin-D levels were less than 20 ng/ml [44]. The prevalence in pregnant Turkish women was 81.4% [47]. In a study of high school students in Iran, the serum mean vitamin-D level was 14.7±9.4 ng/ml [48]. In another study in university students in Shiraz, Iran, 51.2% of female students had low serum levels of vitamin-D [49].

Because the incidence of vitamin-D deficiency in Iran is high and we did not check the serum vitamin-D levels in samples before intervention, it is possible that this dose and duration of vitamin-D prescription was beneficial only for treatment of vitamin-D deficiency and not endometriosis.

In 1072 women attending an infertility center, the prevalence of low serum vitamin-D 3 levels was 89%. Vitamin-D 3 levels were reported to be positively associated with height and endometriosis history [40]. An in vitro study compared the effect of vitamin-D 3 on 25 human endometriosis stromal cell cultures (ovarian endometrioma) with the effect of vitamin-D 3 on culture of 20 endometrial samples of non-endometriosis women; vitamin-D 3 inhibited proliferation, invasion, and proinflammatory cytokine production in endometriosis and reduced production of interleukin 6 and other inflammatory cytokines that stimulate adhesion of endometrial cells to the peritoneal cavity [41].

A study on in vitro effects of vitamin-D 3 on human endometriosis stromal cells found that vitamin-D 3 significantly reduced interleukin 1β and tumor necrotizing factor-α inflammatory responses, and also reported fewer endometrial stromal cells and reduced DNA synthesis. The study found significantly lower serum vitamin-D 3 levels in severe endometriosis compared to normal controls and patients with mild endometriosis [42].

A study in Italy investigated the effect of vitamin-D on primary dysmenorrhea. The samples were 40 women aged 18–40 years old with 4 consecutive painful periods in the past 6 months. They measured the serum levels of 25 hydroxy vitamin-D with high-performance liquid chromatography. Then the women were randomized into a group of 20 women who received a single oral dose of 300000 IU vitamin-D (cholecalciferol) at 5 days before their next menstrual cycle and another group of 20 women received placebo. There was a negative correlation between the baseline dysmenorrhea pain score and the level of 25 hydroxy vitamin-D 3 (r=0.36, p=0.2).

The researchers found a significant reduction of dysmenorrhea pain in the vitamin-D group in comparison with the placebo group in the next 2 menstruations (p<0.01). They suggested this significant reduction of dysmenorrhea pain in vitamin-D prescription group was due to decreased levels of proinflammatory cytokines and decreased the biological activity of prostaglandins [43]. The samples were not assessed for existing endometriosis. Because low levels of serum vitamin-D are common in healthy Italian pre-menopausal women [43], these results only show that vitamin-D was effective in relieving dysmenorrhea at least for 2 months after treatment in women with or without endometriosis and also in women with or without vitamin-D deficiency [50].

Conclusion

There may be a relationship between vitamin-D and pathogenesis of endometriosis, but in our study vitamin-D was not effective in treatment of endometriosis-related pain. Larger clinical trials are needed to determine the possible effects of vitamin-D supplementation in endometriosis treatment.

Study Limitations

The first limitation of this study is the high prevalence of vitamin-D deficiency in our country and worldwide, meaning that a high percentage of our samples may have had vitamin-D deficiency, which may have affected the results of our research. The second limitation is the small sample size of our study.

Further clinical trials are needed on the role of vitamin-D treatment for endometriosis-related pain. Future studies should assess the serum levels of vitamin-D before enrolling study subjects, and those with vitamin-D deficiency should be excluded. Clinical trials with larger sample sizes will be able to produce more reliable results.

REFERENCES

1. Holick MF. Vitamin-D deficiency. N Engl J Med. 2007;357(3):266-281.
2. Hintzpeter B, Mensink GB, Thierfelder W, Müller MJ, Scheidt-Nave C. Vitamin-D status and health correlates among German adults. Eur J Clin Nutr. 2008;62(9):1079-1089.
3. D’Hooghe TM. Endometriosis. In: Berek JS (eds). Berek & Novak’s gynecology. Lippincott Williams & Wlilkins. New York. USA. 2012: 505-557.
4. Viganò P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: Epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):177-200.
5. Koninckx PR, Meuleman C, Demeyere S, Lesaffre E, Cornillie FJ. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Sterill. 1991;55(4):759-765.
6. Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D'Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steri. 2009;92(1):68-74.
7. Esfandiari N, Khazaei M, Ai J, Bielecki R, Gotlieb L, Ryan E, et al. Effect of a statin on an in vitro model of endometriosis. Fertil Steril. 2007;87(2):257-262.
8. Varma R, Rollason T, Gupta JK, Maher ER. Endometriosis and the neoplastic process. Reproduction. 2004;127(3):293-304.
9. Agic A, Xu H, Altgassen C, Noack F, Wolfler MM, Diedrich K, et al. Relative expression of 1,25-dihydroxyvitamin-D 3 receptor, vitamin-D 1 alpha-hydroxylase, vitamin-D 24-hydroxylase, and vitamin-D 25-hydroxylase in endometriosis and gynecologic cancers. Reprod Sci. 2007;14(5):486-497.
10. Almassinokiani F, Mehdizadeh A, Sariri E, Rezaei M, Almasi A, Akbar H, et al. Effects of simvastatin in prevention of pain recurrences after surgery for endometriosis. Med Sci Monit. 2013;19:534-539.
11. Kargar M, Hadjibabaie M, Gholami K. Simvastatin versus triptorelin in prevention of pain recurrences after surgery for endometriosis. Med Sci Monit. 2013;19:858.
12. Olovsson M. Immunological aspects of endometriosis: An update. Am J Reprod Immunol. 2011;66(Suppl 1):101-104.
13. Taylor RN, Hummelshoj L, Stratton P, Vercellini P. Pain and endometriosis: Etiology, impact, and therapeutics. Middle East Fertil Soc J. 2012;17(4):221-225.
14. Lerchbaum E, Rabe T. Vitamin-D and female fertility. Curr Opin Obstet Gynecol. 2014;26(3):145-150.
15. Colonese F, Laganà AS, Colonese E, Sofo V, Salmeri FM, Granese R, et al. The pleiotropic effects of vitamin-D in gynaecological and obstetric diseases: An overview on a hot topic. Biomed Res Int. 2015;2015:986281.
16. Shahrokhi SZ, Ghaffari F, Kazerouni F. Role of vitamin-D in female reproduction. Clin Chim Acta. 2016;455:33-38.
17. Triunfo S, Lanzone A. Potential impact of maternal vitamin-D status on obstetric well-being. J Endocrinol Invest. 2016;39(1):37-44.
18. Nandi A, Sinha N, Ong E, Sonmez H, Poretsky L. Is there a role for vitamin-D in human reproduction? Horm Mol Biol Clin Investig. 2016;25(1):15-28.
19. Chang J, Ye XG, Hou YP, Wu JL, Li SL, Sun QM. Vitamin-D level is associated with increased left ventricular mass and arterial stiffness in older patients with impaired renal function. Med Sci Monit. 2015;21:3993-1399.
20. Cadegiani FA. Remission of severe myasthenia gravis after massive-dose vitamin-D treatment. Am J Case Rep. 2016;17:51–54.
21. Berger U, Wilson P, McClelland RA, Colston K, Haussler MR, Pike JW. Immunocytochemical detection of 1,25-dihydroxyvitamin-D receptors in normal human tissues. J Clin Endocrinol Metab. 1988;67(3):607-613.
22. Calton EK, Keane KN, Soares MJ. The potential regulatory role of vitamin-D in the bioenergetics of inflammation. Curr Opin Clin Nutr Metab Care. 2015;18(4):367-373.
23. Mahon BD, Wittke A, Weaver V, Cantorna MT. The targets of vitamin-D depend on the differentiation and activation status of CD4 positive T-cells. J Cell Biochem. 2003;89(5):922-932.
24. Van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin-D 3: Basic concepts. J Steroid Biochem Mol Biol. 2005;97(1-2):93-101.
25. Nonn L, Peng L, Feldman D, Peehl DM. Inhibition of p38 by vitamin-D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin-D . Cancer Res. 2006;66(8):4516-4524.
26. Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D. Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res. 2005;65(17):7917-7925.
27. Trump DL, Hershberger PA, Bernardi RJ, Ahmed S, Muindi J, Fakih M. Anti-tumor activity of calcitriol: Pre-clinical and clinical studies. J Steroid Biochem Mol Biol. 2004;90(1–5):519-526.
28. Ma Y, Yu WD, Trump DL, Johnson CS. 1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models. Cancer. 2010;116(13):3294-3303
29. Xu J, Li W, Ma J, Liu J, Sha H, Zhou S, et al. Vitamin-D – pivotal nutraceutical in the regulation of cancer metastasis and angiogenesis. Curr Med Chem. 2013;20(33):4109-4120.
30. Abbas MA, Taha MO, Disi AM, Shomaf M. Regression of endometrial implants treated with vitamin-D 3 in a rat model of endometriosis. Eur J Pharmacol. 2013;715(1–3):72–75.
31. Vilarino FL, Bianco B, Lerner TG, Teles JS, Mafra FA, Christofolini DM, et al. Analysis of vitamin-D receptor gene polymorphisms in women with and without endometriosis. Hum Immunol. 2011;72(4):359-363.
32. Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA. Dairy-food, calcium, magnesium, and vitamin-D intake and endometriosis: A prospective cohort study. Am J Epidemiol. 2013;177(5):420-430.
33. Mesrine S, Clavel-Chapelon F, Boutron-Ruault MC. Re: “Dairy-food, calcium, magnesium, and vitamin-D intake and endometriosis: A prospective cohort study” Am J Epidemiol. 2013;178(4):664–65. [PubMed]
34. Somigliana E, Panina-Bordignon P, Murone S, Lucia PD, Vercellini P, Vigano P. Vitamin-D reserve is higher in women with endometriosis. Hum Reprod. 2007;22(8):2273-2278.
35. Parazzini F, Viganò P, Candiani M, Fedele L. Diet and endometriosis risk: A literature review. Reprod Biomed Online. 2013;26(4):323-336.
36. Speeckaert MM, Speeckaert R, van Geel N, Delanghe JR. Vitamin-D binding protein: A multifunctional protein of clinical importance. Adv Clin Chem. 2014;63:1–57.
37. Hwang JH, Wang T, Lee KS, Joo JK, Lee HG. Vitamin-D binding protein plays an important role in the progression of endometriosis. Int J Mol Med. 2013;32(6):1394-1400.
38. Sayegh L, Fuleihan Gel-H, Nassar AH. Vitamin-D in endometriosis: A causative or confounding factor? Metabolism. 2014;63(1):32–41
39. Borkowski J, Gmyrek GB, Madej JP, Nowacki W, Goluda M, Gabryś M, et al. Serum and peritoneal evaluation of vitamin-D -binding protein in women with endometriosis. Postepy Hig Med Dosw 2008;62:103-119.
40. Cho S, Choi YS, Yim SY, Yang HI, Jeon YE, Lee KE, et al. Urinary vitamin-D -binding protein is elevated in patients with endometriosis. Hum Reprod. 2012;27(2):515-522.
41. Mariani M, Viganò P, Gentilini D, Camisa B, Caporizzo E, Lucia PD, et al. The selective vitamin-D receptor agonist, elocalcitol, reduces endometriosis development in a mouse model by inhibiting peritoneal inflammation. Hum Reprod. 2012;27(7):2010-2019.
42. Pagliardini L, Vigano’ P, Molgora M, Persico P, Salonia A, Vailati SA, et al. High prevalence of vitamin-D deficiency in infertile women referring for assisted reproduction. Nutrients. 2015;7(12):9972-9984.
43. Delbandi AA, Mahmoudi M, Shervin A, Zarnani AH. 1,25-dihydroxy vitamin-D 3 modulates endometriosis-related features of human endometriotic stromal cells. Am J Reprod Immunol. 2016;75(4):461-473.
44. Miyashita M, Koga K, Izumi G, Sue F, Makabe T, Taguchi A. Effects of 1,25-dihydroxy vitamin-D 3 on endometriosis. J Clin Endocrinol Metab. 2016;101(6):2371-2379.
45. Lasco A, Catalano A, Benvenga S. Improvement of primary dysmenorrhea caused by a single oral dose of vitamin-D : Results of a randomized, double-blind, placebo-controlled study. Arch Intern Med. 2012;172(4):366-367.
46.  Hintzpeter B, Mensink GB, Thierfelder W, Müller MJ, Nave CS. Vitamin-D status and health correlates among German adults. Eur J Clin Nutr. 2008;62(9):1079-1089.
47. Goswami R, Mishra SK, Kochupillai N. Prevalence & potential significance of vitamin-D deficiency in Asian Indians. Indian J Med Res. 2008;127(3):229-238.
48. Hintzpeter B, Mensink GB, Thierfelder W, Müller MJ, Nave CS. Vitamin-D status and health correlates among German adults. Eur J Clin Nutr. 2008;62(9):1079-1089.
49. Ergür AT, Berberoğlu M, Atasay B, Şıklar Z, Bilir P, Arsan S, et al. Vitamin-D deficiency in Turkish mothers and their neonates and in women of reproductive age. J Clin Res Pediatr Endocrinol. 2009;1(6):266-269.
50. Faghih S, Abdolahzadeh M, Mohammadi M, Hasanzadeh J. Prevalence of vitamin-D deficiency and its related factors among university students in Shiraz, Iran. Int J Prev Med. 2014;5(6):796–99.