Association Between Vitamin D and the Risk of Uterine Fibroids
Phase: NA
Conditions: Gynaecological Disease, Vitamin D Deficiency, Uterine Fibroids
Sponsor: Second Affiliated Hospital of Wenzhou Medical University

 
Association between vitamin D and the risk 
of uterine fibroids 
 
 
 
 
2018.3.16

Study objectives The primary objective of this part is to assess the efficacy of 
supplementation with vitamin D on decreasing the risk of incident uterine fibroids in 
one year and two years. The secondary objective of this study is to evaluate the safety 
of supplementation with vitamin D in subjects. 
 Trial design This is an open-label, randomised controlled trial. After signing of 
informed consent, hypovitaminosis D patients (12 ng/ml ≤ serum 25-hydroxyvitamin 
D3 < 20 ng/ml) without uterine fibroids will be randomly assigned in a 1:1 ratio to 
intervention group or control group. Intervention group will receive an oral dose of 
1600IU/day vitamin D3 for up to 2 years. Control group will receive 2 years follow-up. 
Gynecologic ultrasound examinations will be performed every six months. The mount, 
location and size of the uterine fibroids will be documented. The safety of subjects 
will be evaluated, including blood routine examination, electrolyte, hepatic and renal 
function, liver and urinary system ultrasound, and serum 25-hydroxyvitamin D3. 
Vitamin D receptor genotype of all patients will be tested. Vitamin D3 Drops (soft 
capsules) are purchased from Sinopharm star shark pharmaceutical (xiamen) co., LTD 
and can be preserved for 2 years. An overview of the study design is shown in Figure 
1 and in Table 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: flow diagram. 
 
Table 1:time of date collection 
 
 
 
 
 
 
 
 
 
Follow-up 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Months 
0 
3 
6 
9 
12 
15 
18 
21 
24 
The form of follow-up 
Out-patient 
Informed consent 
x 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
Physical examination 
x 
 
 
 
 
 
 
 
 
Serum 25-hydroxyvitamin D3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Entrollment 
Exclusion 
Control group 
Intervention group 
Two years follow-up 
Outcomes assessment at 12 and 24 months 
Statistical analysis 

Gynecologic ultrasound 
x 
 
x 
 
x 
 
x 
 
x 
Hepatic and renal function 
x 
 
x 
 
x 
 
x 
 
x 
Electrolyte 
x 
 
x 
 
x 
 
x 
 
x 
Blood routine examination 
x 
 
x 
 
x 
 
x 
 
x 
Liver and urinary  
System ultrasound 
x 
 
 
 
x 
 
 
 
x 
Side-effect assessment 
 
x 
x 
x 
x 
x 
x 
x 
x 
Changes in menstruation 
 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse event assessment 
 
x 
x 
x 
x 
x 
x 
x 
x 
Vitamin D receptor genotype 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample size The planned sample size was based on data from a previous study, in 
which the uterine fibroids incidence was 1.278% per year in Asia and 3.745% per year 
in African-American women. Women over the age of 40 years were more likely to 
have uterine fibroids. A study also revealed that African-American females had lower 
level of serum 25-hydroxyvitamin D3 as compared to Caucasian females. Vitamin D 
deficiency was shown to increase the risk of uterine fibroids in vitro, in vivo animal 
models and in clinical trials. We assumed an one-tailed α error of 0.05 and a power 
(1-β) of 0.8. If the rates were 3.745% for the control group and 1.278% for the 
intervention group, we propose to enroll 1160 participants (580 randomized to each 
arm) and allow for a dropout rate of 10% for an effective sample size of 1054.  
Inclusion criteria 
1. Volunteer to participate in the study with informed consent; 
2. Females aged 35-50 who are confirmed with a normal, fibroid-free uterine structure, 
by means of transvaginal or abdominal ultrasonography; 
3. Serum25-hydroxyvitamin D3 <20 ng/ml, ≥ 12ng/ml. 
 Exclusion criteria 
1.Use of sexual hormone, mifepristone, gonadotropin-releasing hormone agonist 
(GnRHa), or other medication which is likely to interfere with uterine fibroids within 
3 months; 
2. Pregnancy, lactation, postmenopause, or planned pregnancy within two years; 
3. Allergic to vitamin D3; 
4. Suspected or identified as other tumors of genital tract; 
5. History of hysterectomy or myomectomy; 
6. History of osteoporosis or vitamin D deficiency taking vitamin D supplements 
within previous one month; 
7. History of hyperparathyroidism, infectious diseases (tuberculosis, AIDS), 
autoimmune diseases, or digestive system diseases (malabsorption, crohn disease and 
dysentery); 
8. Alanine aminotransferase (ALT) or aspartate transaminase (AST) more than 3 times 
of the normal upper limit, total bilirubin (TBIL) more than 2 times of the normal 
upper limit; 
9. Creatinine levels ≥ 1.4 mg/dL (123μmol/L) or creatinine clearance ≤ 50 ml/min; 

10. History of malignant tumors; 
11. Simultaneous participation in another clinical study with investigational medicinal 
product(s) or researcher thinks the subjects are not suitable for this trial. 
Outcomes measures  
The primary outcome is first diagnosis of uterine fibroids in different groups.  
The secondary outcomes include hypercalcemia, abnormal liver and renal function, 
and urinary calculus in different groups.  
Withdrawal Subjects must be withdrawn from the study when one of the following 
criteria occurs: 
1. At their own request. At any time during the study and without giving reasons, a 
subject may decline to participate further. The subject will not suffer any 
disadvantages as a result; 
2. In the investigator's opinion, continuation of the study treatment would be harmful 
to the subject's health; 
3. Obvious non-compliance; 
4. Lost to follow-up; 
5. Pregnancy; 
6. Other medical or surgical treatments of uterine fibroids. 
7. Receive other medical treatments which may affect the level of serum 
25-hydroxyvitamin D3 or other surgical treatments. 
8. The level of serum calcium > 3.5 mmol/L or serum 25-hydroxyvitamin D3 > 100 
ng/mL. 
Safety assessments Safety will be assessed by renal and liver function test, 
electrolyte, routine blood test, and serum 25-hydroxyvitamin D3. Urine pregnancy test 
and serum 25-hydroxyvitamin D3 level will be detected every three months. Other 
indicators are detected during the period of screening and after the treatment of every 
six months. Liver and urinary system ultrasound will be conducted after the treatment 
of 12 months and 24 months. The occurrence of any adverse events in trial 
participants will be recorded in the case report forms during each patient visit. We will 
withdraw patients who have severe adverse events, as it is unsafe for them to continue 
the trial. Meanwhile, we will give them relevant medical care and follow them up 
until the reaction has terminated.