Menstrual Pain (PMS) reduced by vitamin D – RCT 2012, 2014, 2016

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Dysmenorrhea treated by 50,000 IU of Vitamin D weekly - RCT May 2016

The effect of vitamin D on primary dysmenorrhea with vitamin D deficiency: a randomized double-blind controlled clinical trial.
Gynecol Endocrinol. 2016 May 5:1-4. [Epub ahead of print]
Moini A1,2, Ebrahimi T1, Shirzad N3,4, Hosseini R1, Radfar M3,5, Bandarian F6, Jafari-Adli S7, Qorbani M8, Hemmatabadi M4.
1a Department of Gynecology and Obstetrics , Arash Women's Hospital, Tehran University of Medical Sciences , Tehran , Iran .
2b Department of Endocrinology and Female Infertility at Reproductive Biomedicine Research Center , Royan Institute for Reproductive Biomedicine, ACECR , Tehran , Iran .
3c Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran U. of Medical Sciences , Tehran , Iran .
4d Department of Endocrinology , Vali-Asr Hospital, Imam Khomeini Complex Hospital, Tehran University of Medical Sciences , Tehran , Iran .
5e Department of Clinical Pharmacy , Faculty of Pharmacy, Tehran University of Medical Sciences , Tehran , Iran .
6f Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences , Tehran , Iran .
7g Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran U. of Medical Sciences , Tehran , Iran
8h Department of Community Medicine , School of Medicine, Alborz University of Medical Sciences , Karaj , Iran.

Dysmenorrhea is common among women of reproductive age. This study aim was to investigate the effect of vitamin D (vit D) supplementation in treatment of primary dysmenorrhea with vit D deficiency. A randomized double-blind placebo-controlled clinical trial was conducted on 60 women with primary dysmenorrhea and vit D deficiency referred to our clinic at Arash Women's Hospital from September 2013 to December 2014. Eligible women were randomly assigned into treatment and control groups (30 in each group). Individuals in the treatment group received 50 000 IU oral vit D and the control group received placebo weekly for eight weeks. After two months of treatment, there was a significant difference in serum vit D concentration between the two groups (p < 0.001). Pain severity decreased significantly in treatment group after eight weeks of treatment. There was a significant difference in pain intensity between the two groups after eight weeks of treatment and one month after the end of treatment (p < 0.001 for both). A weekly high dose (50 000 IU) oral vit D supplementation for eight weeks in patients with primary dysmenorrhea and vit D deficiency could improve pain intensity.

PMID: 27147120

25,000 IU of Vitamin D every 2 weeks reduced PMS - RCT Aug 2016

Vitamin D Supplementation for Premenstrual Syndrome-Related Mood Disorders in Adolescents with Severe Hypovitaminosis D
Startred with a loading dose of 200,000 IU
J Pediatr Adolesc Gynecol. 2016 Aug;29(4):357-61. doi: 10.1016/j.jpag.2015.12.00

anxiety score 51 ==> 20
irritability score 130 ==> 70
Crying easily41 ==>30
sadness 51 ==> 31,
disturbed relationships150 ==> 70

Dysmenorrhea treated by single dose of 300,000 IU - RCT Feb 2012

Improvement of Primary Dysmenorrhea Caused by a Single Oral Dose of Vitamin D: Results of a Randomized, Double-blind, Placebo-Controlled Study
Feb 27, 2012, Vol 172, No. 4 >
Antonino Lasco, MD; Antonino Catalano, MD; Salvatore Benvenga, MD
Arch Intern Med. 2012;172(4):366-367. doi:10.1001/archinternmed.2011.715

VitaminDWiki Observations
  • None of the women supplemented with vitamin D needed ANY NSAID pain killers
  • This study used a single dose of 300,000 IU of vitamin D
  • 40% in placebo group needed NSAID pain killers at least once (and had NO decrease in pain score)
  • Weekly or monthly doses would have given even more pain reduction and on an on-going basis.
    5,000 or 10,000 IU (300,000 / 60 or 30 days) would be a good starting point for a maintenance dose.
    A loading dose would probably be needed to get quick results if the woman was in a group which would be at high risk of being vitamin D deficient (obese, dark skin, recent pregnancy, etc)


Primary dysmenorrhea is a common disorder characterized by painful uterine cramping, just before or during menstruation, in the absence of any pelvic pathologic conditions. It is frequently accompanied by other symptoms such as nausea, vomiting, diarrhea, asthenia, and insomnia.1 - 2 Primary dysmenorrhea affects almost half of menstruating women, often resulting in school and work absenteeism with major educational and economic consequences.2

An excessive uterine production of prostaglandins (PGs) is the pathogenetic trigger of dysmenorrhea. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the currently accepted drugs for the management of this disorder.1 - 2

Because the vitamin D receptor is widespread and the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin D3 (25[OH]D)-1?-hydroxylase (1?-OHase), which catalyzes the synthesis of 1?,25-dihydroxyvitamin D3 (1,25[OH]2D) from its precursor 25(OH)D, is expressed in the human uterus and in immune system cells, and because vitamin D reduces the synthesis of PGs, a beneficial effect of vitamin D in the uterus pathophysiology is possible.3 - 4

The aim of this prospective intervention study was to evaluate the effect of a single-loading oral dose of cholecalciferol (300 000 IU) on primary dysmenorrhea.

METHODS
Forty women aged 18 to 40 years, attending the outpatient clinics of the Department of Internal Medicine of the University of Messina, Messina, Italy, for primary dysmenorrhea were enrolled. Patients were included if (1) their menstrual cycles lasted 21 to 35 days, with menstruation lasting 3 to 7 days; (2) they experienced at least 4 consecutive painful periods in the past 6 months with the pain starting one day before or on the day of onset of bleeding; (3) they showed a 25(OH)D serum level, measured with high-performance liquid chromatography, below the upper limit of the lowest quartile (<45 ng/mL) (to convert to nanomoles per liter, multiply by 2.496) obtained by dividing the normal range of our laboratory (20-120 ng/mL) into 4 parts. Patients had to be in good health and taking no medications including calcium, vitamin D, and oral contraceptives. Previous and current use of intrauterine contraceptive devices within the 6 months prior to enrollment was not permitted. During the observation period, patients used an accepted means of birth control. Use of NSAIDs was permitted and it had to be recorded in a sheet given to each woman.

Women were randomized into 2 groups: 20 women received a single oral dose of cholecalciferol (300 000 IU/1 mL [Abiogen Pharma S.P.A.]) 5 days before the putative beginning of their next menstrual cycle, while another 20 women received placebo.

The primary outcome was the intensity of menstrual pain as measured by a visual analog scale. The secondary outcome was use of NSAIDs during the 2-month duration of the study. The study was performed between October 2009 and May 2010 according to the Principles of the Declaration of Helsinki. Written informed consent was obtained from each woman.

Comparisons between groups were performed by the unpaired t test or Mann-Whitney test, and within-group comparisons were determined with the paired t test or Wilcoxon matched paired rank sum test for paired data, as appropriate. The Fisher exact test was used to calculate differences in the proportion of categorical variables. Pearson correlation coefficient was calculated to evaluate the correlation between 2 variables. P <.05 was considered significant.

RESULTS
The 2 groups did not differ significantly in age, body mass index, severity of pain, and 25(OH)D levels at baseline. There was a negative correlation between the pain score at baseline and the levels of 25(OH)D (r = ?0.36; P = .02). We observed a significant reduction of pain in the vitamin D group compared with the placebo group (P < .001) over the 2-month duration of our study (Figure). The greatest reduction of pain score was seen in women with severe pain at baseline in vitamin D group (r = ?0.76; P < .001).
We recorded no NSAID use in vitamin D group at 1 and 2 months, while 40% of women in placebo group took NSAIDs at least once (P = .003).

Figure. Changes in mean (SD) pain score in the placebo-treated (A) and vitamin D–treated (B) groups over the 60 days of the study. Eligible women reported intensity of pain on a visual analog scale (VAS) at baseline and then at the end of the first and second month after the dose of placebo or vitamin D. The filled circles in the right panels represent individual changes. Both placebo and vitamin D groups were homogeneous for age (mean [SD], 27 [6.01] y vs 26.3 [6.23] y), body mass index (mean [SD], 21.17 [2.15] vs 21.96 [2.06] [calculated as weight in kilograms divided by height in meters squared]), baseline 25-hydroxyvitamin D3 levels (mean [SD], 29.97 [7.62] ng/mL vs 27.19 [7.53] ng/mL [to convert to nanomoles per liter, multiply by 2.496]), and baseline VAS pain score (mean [SD], 5.60 [1.90] vs 5.85 [2.00]).

Calcitriol (1,25[OH]2D) decreases, in vitro, the level of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor 5 and regulates the expression of several key genes involved in the PG pathway causing decreased biological activity of PGs.6

COMMENT
In the present study we used a single high dose of cholecalciferol because it is an inactive and safe precursor of calcitriol and is able to enhance rapidly serum 25(OH)D after 3 days.7

Vitamin D insufficiency is rather common in young, otherwise healthy Italian premenopausal women and particularly among those living in the southern part of the country.8 In our study, low levels of 25(OH)D may in part be justified by the period of sampling (October-May), probably due to reduced sun exposure causing a low endogenous synthesis of vitamin D.

To our knowledge, this is the first study investigating the effect of a single high dose of vitamin D in primary dysmenorrhea. Our data support the use of cholecalciferol in these patients, especially when exhibiting low plasmatic levels of 25(OH)D, and allow these women to limit the use of NSAIDs.

AUTHOR INFORMATION
Correspondence: Dr Lasco, Department of Internal Medicine, University of Messina, Pad C, Third Floor, A.O.U. Policlinico “G. Martino” Via C. Valeria, Messina 98125, Italy (alasco@unime.it).

REFERENCES

  • 1 Dawood MY. Primary dysmenorrhea: advances in pathogenesis and management. Obstet Gynecol. 2006;108(2):428-441 PubMedCrossRef
  • 2 Proctor M, Farquhar C. Diagnosis and management of dysmenorrhoea. BMJ. 2006;332(7550):1134-1138 PubMedCrossRef
  • 3 Viganò P, Lattuada D, Mangioni S, et al. Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system. J Mol Endocrinol. 2006;36(3):415-424 PubMedCrossRef
  • 4 Zehnder D, Bland R, Williams MC, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 ?-hydroxylase. J Clin Endocrinol Metab. 2001;86(2):888-894 PubMedCrossRef
  • 5 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 PubMedCrossRef
  • 6 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 PubMed
  • 7 Cipriani C, Romagnoli E, Scillitani A, et al. Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young subjects with vitamin D deficiency: a prospective intervention study. J Clin Endocrinol Metab. 2010;95(10):4771-4777 PubMedCrossRef
  • 8 Adami S, Bertoldo F, Braga V, et al. 25-hydroxy vitamin D levels in healthy premenopausal women: association with bone turnover markers and bone mineral density. Bone. 2009;45(3): 423-426 PubMedCrossRef


 Download the study with graphics from VitaminDWiki

Comment on “Improvement of Primary Dysmenorrhea Caused by a Single Oral Dose of Vitamin D”
Elizabeth R. Bertone-Johnson, ScD; JoAnn E. Manson, MD, DrPH
Arch Intern Med. 2012;172(4):367-369. doi:10.1001/archinte.172.4.367

Primary dysmenorrhea is among the most common menstrual disorders, occurring in at least 50% of reproductive-age women.1 Dysmenorrhea is characterized by pelvic pain beginning shortly before the onset of menses or at the beginning of menstrual flow and then lasting several days. The disorder results in substantial impairment in normal functioning and is among the most common causes of school and work absenteeism in young women. The main source of pelvic pain is believed to be prostaglandins synthesized from omega-6 fatty acids prior to menses, which control vasoconstriction and uterine contraction. Though nonsteroidal anti-inflammatory drugs (NSAIDs) and oral contraceptives are effective at managing pain in many patients, these medications are not without risks. Given the high prevalence of dysmenorrhea and the long duration over which affected women may suffer, treatment options with fewer adverse effects are needed.

In this issue, Lasco and colleagues2 report findings from a small randomized trial of the effect of high-dose vitamin D therapy on pain associated with primary dysmenorrhea. Forty women seeking treatment were randomized to receive either a single oral dose of 300 000 IU of vitamin D3(cholecalciferol) (n = 20) or a placebo (n = 20), given 5 days before the expected start of their next menstrual period. After 2 months, mean pain scores had decreased 41% from baseline levels among women assigned to vitamin D treatment, while no difference was observed among women assigned to placebo (P < .001). The largest benefits were observed among women reporting the highest pain scores at baseline. Furthermore, women assigned to vitamin D reported no use of NSAIDs to manage pain during the 2-month follow-up period, while 40% of the women assigned to placebo reported NSAID use at least once (P = .003).

While the effect of vitamin D on dysmenorrhea has not been evaluated previously, a small number of studies have suggested a role for vitamin D in other menstrual and pain-related conditions in women, including

  • premenstrual syndrome (PMS),
  • fibromyalgia, and
  • endometriosis.

Low dietary vitamin D intake was associated with the initial development of moderate to severe PMS in a substudy within the prospective Nurses' Health Study II cohort. Bertone-Johnson and colleagues3 (2005) found that women consuming 700 IU/d or more of vitamin D had a significant 41% lower risk of developing PMS over the next 2 to 4 years compared with women consuming approximately 100 IU/d (P value for trend, .01). In a smaller cross-sectional study, women reporting to consume 100 IU/d or more of vitamin D from food sources had 70% lower prevalence of PMS compared with those reporting to consume less than 100 IU/d (95% CI, 0.10-0.98). However, late luteal phase serum 25-hydroxyvitamin D3 (25[OH]D) levels were not associated with prevalence.4

Chronic widespread pain and fibromyalgia syndromes are significantly more prevalent in women than in men, likely owing to the influence of sex steroid hormones.5 Several well-designed observational studies in women have reported inverse associations between fibromyalgia pain and 25(OH)D levels, though results overall have been inconsistent.6 Relatively few studies have evaluated the role of vitamin D in endometriosis, which is a prominent cause of secondary dysmenorrheal and associated pelvic pain. Interestingly, Somigliana and colleagues7 (2007) observed significantly higher 25(OH)D levels among patients with endometriosis compared with controls in a cross-sectional study and a positive correlation between 25(OH)D levels and disease severity, suggesting that the relation between vitamin D and endometriosis is likely complex and not yet well understood.

Vitamin D may have a positive impact on dysmenorrhea and related syndromes through a variety of mechanisms.8 In the endometrium, 1,25-dihydroxyvitamin D (1,25[OH]2D), the bioactive form of vitamin D, decreases prostaglandin synthesis by suppressing expression of cyclooxygenase-2, and increases prostaglandin inactivation by up-regulating 15-hydroxyprostaglandin dehydrogenase. In addition, 1,25(OH)2D down-regulates prostaglandin receptor expression. 1,25(OH)2D may also exert anti-inflammatory effects through other pathways, such as by inhibiting nuclear factor–?B signaling and increasing mitogen-activated protein kinase phosphatase 5 activity, thus blocking cytokine production via p38 activation.

The strong benefit of vitamin D on dysmenorrhea observed by Lasco and colleagues2 provides important support for larger, long-duration randomized trials of vitamin D in the treatment of menstrual pain and other pain-related conditions in women. These trials must address several key issues. First, it is important to know how long reductions in pain associated with a single high-dose vitamin D therapy would persist and how often treatment would need to be repeated. If 300 000 IU is required every 2 months, this would equate to approximately 5000 IU per day, considerably higher than the tolerable upper intake level set by the Institute of Medicine of 4000 IU/d.9 Each single dose would need to be effective for multiple months for average daily vitamin D intake to remain below this level. Furthermore, because treatment for menstrually related conditions may be necessary throughout the premenopausal years, follow-up of participants in clinical trials of vitamin D must be extended to better evaluate adverse effects and compare risks and benefits. This is especially pertinent given the findings reported by Sanders and colleagues10 (2010), who observed increased risks of fracture and falls among older women treated with a single 500 000 IU dose annually over 3 to 5 years, especially within the first 3 months after treatment. A third consideration is the baseline serum level of 25(OH)D at which supplementation may be beneficial. Women eligible for the present trial were those with 25(OH)D levels in the lower quartile of the laboratory's normal range. It thus remains unknown whether improvements in dysmenorrhea pain would be observable among women with higher baseline 25(OH)D levels.

If these findings are confirmed in future randomized trials, vitamin D supplementation may become an important new treatment option for women who experience menstrual pain disorders. In the meantime, encouraging all women to obtain the recommended dietary allowance for vitamin D (?600 IU/d for women of reproductive age),10 as well as screening for low serum 25(OH)D levels among women with other risk factors for vitamin D deficiency, would be a rational interim approach.

AUTHOR INFORMATION
Correspondence: Dr Manson, Division of Preventive Medicine, Department of Epidemiology, Brigham and Women's Hospital, 900 Commonwealth Ave, Third Floor, Boston, MA 02215 (jmanson@rics.bwh.harvard.edu).

Financial Disclosure: None reported.

Funding/Support: Dr Manson and colleagues at Brigham and Women's Hospital, Harvard Medical School, are recipients of funding from the National Institutes of Health to conduct the VITamin D and OmegA-3 TriaL (VITAL), a large-scale randomized trial of vitamin D and omega-3s in the prevention of cancer and cardiovascular disease.

REFERENCES

  • 1 Proctor M, Farquhar C. Diagnosis and management of dysmenorrhoea. BMJ. 2006;332(7550):1134-1138 PubMedCrossRef
  • 2 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):ild110011366-367 CrossRef
  • 3 Bertone-Johnson ER, Hankinson SE, Bendich A, Johnson SR, Willett WC, Manson JE. Calcium and vitamin D intake and risk of incident premenstrual syndrome. Arch Intern Med. 2005;165(11):1246-1252 PubMedCrossRef
  • 4 Bertone-Johnson ER, Chocano-Bedoya PO, Zagarins SE, Micka AE, Ronnenberg AG. Dietary vitamin D intake, 25-hydroxyvitamin D3 levels and premenstrual syndrome in a college-aged population. J Steroid Biochem Mol Biol. 2010;121(1-2):434-437 PubMedCrossRef
  • 5 Manson JE. Pain: sex differences and implications for treatment. Metabolism. 2010;59(suppl 1) S16-S20 PubMedCrossRef
  • 6 Daniel D, Pirotta MV. Fibromyalgia—should we be testing and treating for vitamin D deficiency? Aust Fam Physician. 2011;40(9):712-716 PubMed
  • 7 Somigliana E, Panina-Bordignon P, Murone S, Di Lucia P, Vercellini P, Vigano P. Vitamin D reserve is higher in women with endometriosis. Hum Reprod. 2007;22(8):2273-2278 PubMedCrossRef
  • 8 Krishnan AV, Feldman D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol. 2011;51311-336 PubMedCrossRef
  • 9 Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011
  • 10 Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815-1822 PubMedCrossRef

Another Vitamin D and PMS study April 2014 is attached at bottom of this page

Nurses’ Health Study II, 1989 (back when people had higher levels of vitamin D)
Our research group previously reported that women who consumed approximately 400 IU of vitamin D per day had a significant 40% lower risk of being diagnosed with PMS in the next 2–4 years, as compared to women consuming approximately 100 IU/day

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