Vitamin D for Menstrual and Pain-Related Disorders in Women

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–κB 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.