A placebo-controlled trial tested whether correcting vitamin D deficiency could reduce persistent endometriosis symptoms in women already on hormone therapy, with results that cast doubt on hopes for simple add-on treatment.
Study: Supplemental vitamin D supplementation in women receiving dienogest therapy for endometriosis: a randomized controlled trial. Image credit: Orawan Patarawimonchai / Shutterstock
A recent randomized controlled trial has been accepted for publication in a journal. scientific reportresearchers examined vitamin D supplementation as an adjunct to dienogest (Bellogest) therapy in women with endometriosis. After the 8-week study, participants who received vitamin D had numerically lower adjusted mean scores on pain measures than those who received a placebo. Nevertheless, the difference was neither statistically nor clinically significant, and the therapeutic role of vitamin D needs to be clarified in long-term clinical trials.
Endometriosis affects millions of women worldwide and remains one of the leading causes of infertility. People with this estrogen-dependent condition experience debilitating pelvic pain due to the growth of endometrioid glands and stroma beyond the uterine cavity. These lesions are most commonly found in the pelvic peritoneum and ovaries, but can also occur in extrapelvic sites, such as the intestines and diaphragm, and are associated with local inflammation, immune dysregulation, and chronic pain.
Vitamin D has been proposed as a potential treatment option for patients with endometriosis due to its effects on immune regulation. In animal models, vitamin D reduced the area of endometriotic lesions and decreased fibrosis. Vitamin D3 also inhibited interleukin-1β and tumor necrosis factor-α responses in cultured human endometrial stromal cells. Nevertheless, clinical trials have shown mixed results. These preclinical observations have not yet translated into consistent clinical benefits for patients.
About research
In this single-center, randomized, double-blind, placebo-controlled trial, researchers investigated whether vitamin D supplementation could reduce pain and improve quality of life (QoL) in women receiving dienogest therapy for endometriosis in 2023-2024.
The study enrolled 66 sexually active married women with symptomatic endometriosis, defined as a visual analogue scale score of at least 4, and vitamin D deficiency, defined as a serum 25-hydroxyvitamin D less than 30 ng/mL, as confirmed by a gynecologist. Diagnosis was made according to the European Society of Human Reproduction and Embryology (ESHRE) 2022 guidelines, based on a combination of clinical examination, medical history, transvaginal ultrasound and magnetic resonance imaging (MRI), or previous laparoscopic confirmation. None of the participants had used vitamin D supplements in the past 3 months or had comorbidities such as hypertension, thyroid disease, diabetes, Cushing’s syndrome, or hyperprolactinemia.
The research team randomly assigned participants in a 1:1 ratio to receive vitamin D supplements (n = 33, intervention group, 4,000 IU every other day) or a placebo (n = 33, control group) for 8 weeks. All participants received a stable dose of 2.0 mg dienogest daily for at least 3 months before study initiation and continued treatment throughout the study.
Before and after the study intervention, researchers measured pain severity using a visual analog scale (VAS) and assessed QoL as a secondary outcome using the Endometriosis Health Profile-30 (EHP-30). They assessed changes in EHP-30 domains including pain, control and helplessness, social support, emotional well-being, and self-image. In addition, participants completed the Painful Endometriosis Symptoms Questionnaire (ENDOPAIN-4D) as another primary measure of pain symptoms. They also completed a sociodemographic questionnaire providing data on age, education, occupation, income, and obstetric history.
Results and discussion
Baseline demographic and clinical characteristics showed some disparities between the vitamin D and placebo groups. The largest difference was in age, with a standardized mean difference of 0.7. Participants in the intervention group were on average younger (30.7 vs. 35.3 years), but mean body mass index (BMI) was similar between both groups (24.4 vs. 24.7).
After the 8-week study, adjusted intervention ENDOPAIN-4D scores for usual pain averaged 38.8 and 50.1 in the intervention and placebo groups, respectively, with an adjusted mean difference (AMD) of -11.3 and a 95% confidence interval (CI) of -26.2 to 3.5, p=0.136. For worst pain, participants receiving vitamin D had a mean of 23.6 compared to 25.6 for those receiving placebo, AMD -2.0, 95% CI -9.0 to 4.9, p=0.492. Adjusted VAS scores yielded similar results, with lower scores reported by treated individuals compared to those receiving placebo (5.8 vs. 6.2), -0.3 for AMD, 95% CI -1.3 to 0.5, p = 0.113.
Although participants receiving vitamin D reported numerically lower pain scores, none of the adjusted group differences in pain or QoL outcomes were statistically significant. No significant differences were observed among the five EHP-30 domains, and the difference between adjusted VAS and EHP-30 remained below the reported threshold of clinical significance. These findings do not prove that vitamin D supplementation is effective in reducing pain.
Sensitivity analyzes showed that adjusting for baseline sociodemographic differences did not substantially change the null results. Meanwhile, both study treatments appeared to be generally well tolerated, with no serious adverse events reported during the trial. Across the study population, a small number of participants experienced mild symptoms such as nausea, dizziness, fatigue, constipation, and diarrhea.
The authors proposed that background dienogest therapy may cause a “floor effect,” suppressing symptoms before adding vitamin D, thereby masking the potential benefits of vitamin D. Furthermore, the researchers did not perform repeated measurements of serum 25-hydroxyvitamin D after the intervention to verify whether the supplement achieved biochemical replenishment among study participants. If some people remained below their target vitamin D levels despite taking supplements, that may have affected the results.
Generalizability was also limited by the small, single-center convenience sample, inclusion of only married sexually active women, lack of stratification by endometriosis subtype, and lack of control for diet and UV exposure.
conclusion
The results of this study show that 8 weeks of supplemental vitamin D did not result in statistically or clinically significant improvements in pain or QoL compared with placebo in women on stable dienogest therapy. Therefore, the results of this study do not support the routine use of short-term vitamin D supplementation as an adjunct to dienogest. However, larger trials with longer follow-up are needed to determine whether responses differ depending on long-term treatment or specific endometriosis phenotypes.
In future studies, researchers should include measurement of post-intervention serum vitamin D levels, evaluate individualized dosing strategies, and examine outcomes across different endometriosis subtypes for a more comprehensive evaluation. Because this study evaluated vitamin D as an add-on treatment, it cannot be established whether vitamin D is effective as a sole treatment.
Reference magazines:
- Shabani, F., Hajizadeh, K., Hesami, M. et al. (2026). Supplemental vitamin D supplementation in women receiving dienogest therapy for endometriosis: A randomized controlled trial. scientific report. Doi: 10.1038/s41598-026-62548-6 https://www.nature.com/articles/s41598-026-62548-6
