Deficiency of the mitochondrial ribosomal subunit, MRPL50, causes autosomal recessive syndromic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a common cause of infertility in women, characterised by amenorrhea and elevated FSH under the age of 40 years. In some cases, POI is syndromic in association with other features such as sensorineural hearing loss in Perrault syndrome. POI is a heterogeneous disease with over 80 causative genes known so far; however, these explain only a minority of cases. Using whole-exome sequencing (WES), we identified a MRPL50 homozygous missense variant (c.335T > A; p.Val112Asp) shared by twin sisters presenting with POI, bilateral high-frequency sensorineural hearing loss, kidney and heart dysfunction. MRPL50 encodes a component of the large subunit of the mitochondrial ribosome. Using quantitative proteomics and western blot analysis on patient fibroblasts, we demonstrated a loss of MRPL50 protein and an associated destabilisation of the large subunit of the mitochondrial ribosome whilst the small subunit was preserved. The mitochondrial ribosome is responsible for the translation of subunits of the mitochondrial oxidative phosphorylation machinery, and we found patient fibroblasts have a mild but significant decrease in the abundance of mitochondrial complex I. These data support a biochemical phenotype associated with MRPL50 variants. We validated the association of MRPL50 with the clinical phenotype by knockdown/knockout of mRpL50 in Drosophila, which resulted abnormal ovarian development. In conclusion, we have shown that a MRPL50 missense variant destabilises the mitochondrial ribosome, leading to oxidative phosphorylation deficiency and syndromic POI, highlighting the importance of mitochondrial support in ovarian development and function.

Thyroid Function Abnormalities and Outcomes in Hospitalized Patients with COVID-19 Infection: A Cross-Sectional Study.

Thyroid gland can be affected by the COVID-19 infection. The pattern of thyroid function abnormality reported in COVID-19 is variable; in addition, some drugs used in COVID-19 patients like glucocorticoids and heparin can affect the thyroid function tests (TFT). We conducted an observational, cross-sectional study of thyroid function abnormalities with thyroid autoimmune profile in COVID-19 patients with varying severity from November 2020 to June 2021. Serum FT4, FT3, TSH, anti-TPO, and anti-Tg antibodies were measured before the initiation of treatment with steroids and anti-coagulants. A total of 271 COVID-19 patients were included in the study, of which 27 were asymptomatic and remaining 158, 39, and 47 were classified to mild, moderate and severe categories, respectively, according to MoHFW, India criteria. Their mean age was 49±17 years and 64.9% were males. Abnormal TFT was present in 37.2% (101/271) patients. Low FT3, low FT4, and low TSH were present in 21.03%, 15.9% and 4.5% of patients, respectively. Pattern corresponding to sick euthyroid syndrome was the most common. Both mean FT3 and FT3/FT4 ratio decreased with increasing severity of COVID-19 illness (p=0.001). In multivariate analysis, low FT3 was associated with increased risk of mortality (OR 12.36, 95% CI: 1.23-124.19; p=0.033). Thyroid autoantibodies were positive in 58 (27.14%) patients; but it was not associated with any thyroid dysfunction. Thyroid function abnormality is common among COVID-19 patients. Both low FT3 and FT3/FT4 ratio are indicators of disease severity while low FT3 is a prognostic marker of COVID-19 associated mortality.

Diagnosis and treatment outcomes of Cushing's disease during pregnancy.

PURPOSE: We report a case of a pregnant woman with Cushing's disease (CD) and performed a systematic review of literature on diagnosis, treatment, maternal and fetal outcomes of CD in pregnancy. METHODS: A PubMed search was performed for manuscripts in English language from inception till June 2020. Cases of CD with hypercortisolism during pregnancy were included and categorized into three groups based on treatment received. Data on diagnostic modalities, CD remission, materno-fetal outcomes were analysed. RESULTS: Fifty-five patients of CD with 62 pregnancies were analysed. 24-h urinary free cortisol(UFC) was elevated by a mean of 5.4 ± 4.2 fold upper limit of normal non-pregnant level. 12/19 (63.1%) CD patients had more than threefold elevation of UFC measured during pregnancy. Mean midnight serum cortisol was 753.7 ± 270.5 nmol/l. At a midnight serum cortisol cut off of 440 nmol/l, 15/16 patients were correctly identified as CD. 23.2% underwent trans-sphenoidal surgery (group 1), 16.1% received only medical treatment (group 2) while 60.7% received no treatment (group 3) during pregnancy. Remission rates for CD in groups 1 and 2 were 76.9% and 77.8%, respectively. Adverse maternal and fetal outcomes were seen in 53.9% and 59.3% of the patients, respectively and were not significantly different between groups, although, lesser live births and greater pregnancy losses were seen in group 3. CONCLUSION: Midnight serum cortisol had better sensitivity than UFC for diagnosing hypercortisolism due to CD during pregnancy. In general, CD should be treated during pregnancy in order to optimize maternal and fetal outcomes as a trend towards increased live births is seen in treated subjects.

Effect of Curcuma longa on vascular function in native Tamilians with type 2 diabetes mellitus: A randomized, double-blind, parallel arm, placebo-controlled trial.

Diabetes mellitus is characterized by increased central arterial stiffness and endothelial dysfunction leading to increased risk of cardiovascular complications. The aim of this study is to evaluate the effect of Curcuma longa on arterial stiffness and endothelial dysfunction in patients with type 2 diabetes mellitus. This randomized controlled trial was conducted in 136 patients of type 2 diabetes. Among them, 114 completed at least one follow-up visit and included for data analysis. Arterial stiffness parameters were measured at baseline and every month for 3 months and endothelial dysfunction markers at baseline and after 3 months of treatment with C. longa or placebo. These parameters were compared between the two groups. Both C. longa and placebo groups were comparable at baseline. After 3 months of treatment, C. longa produced significant reduction from baseline in carotid-femoral pulse wave velocity (p = .002), left brachial-ankle pulse wave velocity (p = .001), aortic augmentation pressure (p = .007), aortic augmentation index (p = .007), and aortic augmentation index at heart rate 75 (p = .018) as compared with the placebo group. Three months treatment with C. longa significantly decreases arterial stiffness as compared with placebo in type 2 diabetes mellitus patients.

Effect of Frey's procedure on islet cell function in patients with chronic calcific pancreatitis.

BACKGROUND: Frey's procedure involves both drainage and resection of the pancreas in subjects with chronic calcific pancreatitis (CCP). The procedure may affect the pancreatic endocrine function after surgery. The present study was to evaluate the effect of Frey's procedure on both beta and alpha cell function in CCP patients. METHODS: Thirty CCP patients who underwent Frey's procedure were included. According to the glycemic status, patients were divided into the diabetes mellitus (DM), prediabetes, and normal glucose tolerance (NGT) groups. Islet cell function was assessed before and 3 months after surgery. RESULTS: At baseline, there was a significant difference in beta cell function among the three groups [NGT group 1.71 (1.64-2.07) vs prediabetes group1.50 (0.83-1.61) vs DM group 0.33 (0.12-0.55), P < 0.0001], but the insulin resistance was not different among them. Post glucose hyperglucagonemia representing alpha-cell dysfunction during oral glucose tolerance test was present in all of them, but showed no significant difference [NGT group 0.15 (0.06-0.31) vs prediabetes group 0.32 (0.05-0.70) vs DM group 0.07 (0.02-0.18), P = 0.20]. Frey's procedure did not change beta cell function and insulin resistance. However, alpha-cell dysfunction deteriorated after surgery [0.10 (0.03-0.27) vs 0.33 (0.09-0.68), P = 0.004]. CONCLUSIONS: Although Frey's procedure does not affect the beta cell function and insulin resistance in CCP patients, the alpha-cell dysfunction deteriorates after surgery.

Predictors for antenatal insulin requirement in gestational diabetes.

The purpose of this study was to identify pre-gestational and gestational factors predicting subsequent insulin requirement in patients with gestational diabetes mellitus (GDM). Maternal parameters were compared between mothers achieving glycemic control with or without the addition of antenatal insulin therapy (AIT). Insulin was required only in 8/83 (10%) patients for glycemic control. Those who needed insulin had a stronger family history of diabetes and higher first hour plasma glucose along with multiple (>1) abnormal values during oral glucose tolerance test (OGTT) in univariate analysis (p < 0.05). The first hour plasma glucose value of ≥ 9.72 mmol/l predicted requirement of AIT in GDM mothers with a sensitivity of 100% and specificity of 73%. However, only positive family history of diabetes mellitus among first degree relatives and multiple abnormal values in OGTT were independent predictors for antenatal insulin requirement in regression analysis.

Male Hypogonadism After Recovery from Acute COVID-19 Infection: A Prospective Observational Study.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 can affect the hypothalamic-pituitary-gonadal axis (HPG) due to the expression of the angiotensin-converting enzyme 2 receptor. OBJECTIVES: To assess the prevalence of hypogonadism and Sertoli cell dysfunction in coronavirus disease 2019 (COVID-19) male survivors. METHOD: Male subjects recovered from acute COVID-19 infection were prospectively observed. The primary outcomes included the proportion of hypogonadism, defined biochemically as serum testosterone<230 ng/dL or CFT of<6.4 ng/mL if the total testosterone is between 230-320 ng/m. Sertoli cell dysfunction was defined as inhibin-B level<54.5 pg/mL. Subjects with hypogonadism were followed up at 12 months to assess the recovery of the HPG axis. RESULTS: Eighty-three subjects aged≥18 years were evaluated at a median of 120 (±35) days post-recovery. Their mean age was 49.50±12.73 years, and the mean BMI was 26.84±5.62 kg/m2. Low testosterone was detected in 21 (24.71%) and low inhibin-B was detected in 14 (19.71%) out of 71 subjects at 3 months. Subjects with low testosterone were younger, with a mean age of 43.29±12.03 years (P-0.08) and higher BMI (P-0.012). The severity of COVID-19 infection, duration of hospitalization, and other factors were not significantly associated with low testosterone. At 12 months, 18 out of 21 subjects came for follow-up, of which 9 (50%) showed persistently low testosterone, suggestive of hypogonadism. CONCLUSION: Following COVID-19 infection, testosterone levels recovered over time; however, a significant proportion of subjects had low levels at 12-month follow-up. These findings have long-term implications for the management of COVID-19 subjects.

Clinical, Hormonal, and Genetic Spectrum of 46 XY Disorders of Sexual Development (DSD) Patients.

OBJECTIVES: To evaluate the clinical, hormonal and genetic characteristics of 46XY disorders of sexual development (DSD) patients from South India. METHODS: 46XY DSD patients with a provisional diagnosis of 17ß-hydroxysteroid dehydrogenase 3 (17BHSD3) deficiency, 5 alpha-reductase type 2 deficiency (5ARD2) or partial androgen insensitivity syndrome (PAIS) based on clinical and hormonal analysis were included in this study. All the patients underwent detailed clinical and hormonal evaluations. Targeted next-generation sequencing for all three genes (AR, HSD17B3, and SRD5A2) in parallel was carried out for all the included patients and their parents. RESULTS: Based upon the clinical and hormonal analysis, among the 37 children with 46XY DSD in the present study, 21 children were diagnosed with 5ARD2, 10 with PAIS, and six with 17BHSD3 deficiency. However, genetic analysis revealed pathogenic mutations in nine patients - six in the AR gene, two in the SRD5A2 gene, and one in the HSD17B3 gene. The concordance rate between provisional hormonal and genetic diagnosis was only 22.2%. Two out of six subjects with AR gene variants were positive for somatic mosaicism. CONCLUSIONS: In the present study, a positive genetic diagnosis was detected in nine patients (24%), including five novel variants. In this study, mutations in the AR gene was the most reported. The authors did not find the testosterone: dihydrotestosterone (T: DHT) ratio to be an accurate hormonal diagnostic tool.

Insulin Sensitivity, Islet Cell Function, and Incretin Axis in Pregnant Women With and Without Gestational Diabetes Mellitus.

Introduction: The aim of this study was to compare insulin sensitivity, islet cell function, and incretin axes in pregnant subjects with GDM and normal healthy controls. Methods: Pregnant women at 24 to 28 weeks of gestation were subjected to a 75 g oral glucose tolerance test (OGTT). Samples for glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were collected at 0, 30, 60, and 120 min during the OGTT. The Matsuda index (MI) and insulin secretion and sensitivity index-2 (ISSI-2) were assessed. The glucagon suppression index (GSI) was calculated along with the area under the curve (AUC) for glucose, insulin, glucagon, GLP-1, and GIP. Results: A total of 48 pregnant women (25 GDM and 23 controls) were finally analysed. The MI and ISSI-2 were low in the GDM group [4.31 vs. 5.42; P = 0.04], [1.99 vs. 3.18, P ≤ 0.01] respectively). Total AUCglucagon was higher in the GDM group (7411.7 vs. 6320.1, P = 0.02). GSI30 was significantly lower in the GDM group (-62.6 vs. -24.7, P = 0.03). Fasting GLP-1 levels were low in GDM women (17.3 vs. 22.2, P = 0.04). The total AUCGLP-1 positively correlated with total GSI in the GDM group. Conclusion: Asian-Indian GDM women have high insulin insensitivity, islet cell dysfunction, and low fasting GLP-1. Incretin axis dysfunction plays a potential role in their islet cell dysfunction.

Role of bisphosphonates in hypertrophic osteoarthropathy: a systematic review.

BACKGROUND: The role of bisphosphonates (BP) in hypertrophic osteoarthropathy (HPOA) is unclear. We presented a case of primary HPOA and performed a systematic review of literature on the effect of BP on treatment response in primary and secondary HPOA. METHODS: The study was prospectively registered in PROSPERO (CRD42022343786). We performed a PubMed literature search that restricted to the English language. We included patients diagnosed with primary or secondary HPOA who received BP. The primary endpoint assessed was the effectiveness of BP on response to pain or arthritis. Secondary outcomes included timing, degree, and duration of response, comparison to other HPOA therapies, impact of BP on radiology, bone scan, bone turnover markers, and adverse effects of BP. RESULTS: Literature search retrieved only case reports. Forty-five patients (21 primary, 24 secondary HPOA) had received BP. Majority(88.3%) experienced improvement in pain or arthritis. Response was gradual for primary HPOA and within a median of 3 to 7 days for secondary HPOA after treatment with BP. Most patients had reduced bone scan uptake after BP. When other HPOA therapies were tried, half responded to BP after not having previously responded to other therapies, while a third received the treatments concurrently, making it difficult to attribute treatment response to a drug. Reporting of other secondary outcomes was very heterogenous and qualitative to draw conclusions. No major adverse effects have been reported for BP in HPOA. CONCLUSION: Bisphosphonates provide an effective and safe treatment option for primary and secondary HPOA. However, there is a lack of randomized controlled trials.

Growth hormone and gastrointestinal malignancy: An intriguing link.

Growth hormone (GH) excess is associated with several systemic complications, one of which is the increased risk of neoplastic processes particularly of the gastrointestinal (GI) tract. Among the GI neoplasms, the most reported association is with benign and malignant neoplasms of the colon. In the majority of published literature, an increased incidence of GI neoplasms, both colonic adenomas as well as colorectal carcinoma is reported. However, the studies on colon cancer-specific mortality rate are conflicting with recent studies reporting similar cancer-specific mortality rates in comparison to controls. Many studies have reported an association of colorectal neoplasms with GH levels. Pathogenic mechanisms put forward to explain this association of GH excess and GI neoplasms primarily involve the increased GH-insulin-like growth factor 1 (IGF-1) signaling. Both GH and IGF-1 have proliferative, anti-apoptotic, and angiogenic effects on the systemic tissues leading to cellular proliferation. Other contributing factors to the increased risk of GI neoplasms include slow intestinal transit with a redundant large bowel, altered bile acids, deranged local immune response, shared genetic susceptibility factors and hyperinsulinemia. In view of the increased risk association, most guidelines for the care of acromegaly patients recommend an initial screening colonoscopy. Recommendations for further follow-up colonoscopy differ but broadly, the guidelines agree that it depends on the findings at first colonoscopy and state of remission of GH excess. Regarding the concern about the risk of colorectal cancers in patients receiving recombinant GH therapy, most cohort studies do not show an increased risk.

Treatment on Nature's lap: Use of herbal products in the management of hyperglycemia.

Diabetes mellitus (DM) is characterized by persistently elevated blood glucose concentration that lead to multisystem complications. There are about 400 medicinal plants cited to have a beneficial effect on DM. We must choose products wisely based on data derived from scientific studies. However, a major obstacle in the amalgamation of herbal medicine in modern medical practices is the lack of clinical data on its safety, efficacy and drug interaction. Trials of these herbal products often underreport the side effects and other crucial intervention steps deviating from the standards set by Consolidated Standards of Reporting Trials. Due to a lack of knowledge of the active compounds present in most herbal medicines, product standardization is difficult. Cost-effectiveness is another issue that needs to be kept in mind. In this mini-review, we focus on the anti-hyperglycemic effect of herbal products that are commonly used, along with the concerns stated above.

A Randomized Double-Blind Placebo-Controlled Trial Evaluating the Efficacy of Oral Cholecalciferol in Improving Renal and Vascular Functions in Vitamin D-Deficient Patients With Type 2 Diabetes Mellitus.

This study was performed to evaluate the efficacy of cholecalciferol in improving renal and vascular functions in vitamin D-deficient patients with type 2 diabetes mellitus (T2DM) along with chronic kidney disease (CKD). One hundred patients (18 - 65 years), having T2DM along with CKD (stage IIIA and IIIB) and hypovitaminosis D were randomized (1:1) to receive either oral cholecalciferol 60,000 IU (Group A) or placebo (Group B) weekly for 8 weeks along with standard background treatment. They were followed up for another 24 weeks. Various parameters of renal and vascular functions were compared. Except for serum calcium and phosphate levels which were significantly higher in Group A (p < 0.001), there was no significant difference in any of the biochemical or vascular parameters between the two groups at 8 weeks. There were comparable changes in urinary albumin-creatinine ratio and carotid-femoral pulse wave velocity in the two groups at 8 and 24 weeks. There was no improvement in any of the vascular parameters from the corresponding baseline values in the two groups at 8 and 32 weeks. No improvement in renal and vascular functions was observed following treatment with oral cholecalciferol in patients with T2DM and CKD.

Metabolic Bone Disease in Preterm Neonates With Fetal Growth Restriction (FGR): A Prospective Cohort Study.

OBJECTIVE: To study the association of fetal growth restriction (FGR) with metabolic bone disease in preterm neonates. METHODOLOGY: This prospective cohort study included 94 preterm neonates with FGR as cases and an equal number of gestation-matched appropriate for gestational age (AGA) neonates without FGR as controls. The incidence of metabolic bone disease, and serum biochemical markers at various time intervals till 6 months corrected age were compared. The risk factors for metabolic bone disease and its association with stunting at 6 months of corrected age were studied. RESULTS: The incidence of metabolic bone disease, though higher in the FGR neonates (15.5%), was not significantly different from AGA neonates (6.7%) [RR (95%CI) 0.92-5.82; P=0.06]. Birth weight [aOR (95%CI) 0.8 (0.64-0.98); P=0.03] and time to reach full feeds [aOR (95%CI) 1.17 (1.01-1.36); P=0.03] were significantly associated with an increased risk of metabolic bone disease after adjusting for FGR status. Mean (SD) levels of calcium, phosphorus, alkaline phosphatase, parathormone (PTH), and vitamin D were similar in both groups. No significant association existed between metabolic bone disease and stunting at 6 months of corrected age [RR (95%CI) 2 (0.75-5.4); P=0.16]. CONCLUSION: FGR was not found to be significantly associated with metabolic bone disease in preterm neonates.

The Association of Dyslipidemia and Atherogenic Indices With Glycemic Control in Diabetic Dyslipidemia Patients: A Real-World Landscape.

BACKGROUND: Dyslipidemia is an important comorbid factor of type 2 diabetes mellitus (T2DM) that increases the risk of cardiovascular diseases. This study aimed to assess the pattern of dyslipidemia and atherogenic indices and determine its relation with glycemic control. METHODS: A cross-sectional study enrolled 382 patients with diabetic dyslipidemia. The socio-demographics data, clinical features, and laboratory parameters were collected. The baseline lipid parameters such as total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and glycated hemoglobin (HbA1C) were measured. Atherogenic indices such as TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, non-HDL-C/HDL-C and atherogenic index of plasma (AIP) [log10 (TG/HDL-C)] were calculated. T2DM patients were classified into three groups based on the degree of glycemic control: Good glycemic control (HbA1C<7%), fair control (HbA1C 7-8%), and poor control (HbA1C>8%). RESULTS: The population's mean age was 48.60±6.15 years, with 145 (38%) males. We found mixed dyslipidemia as the most prevalent (36.1%) form of dyslipidemia in our patients. The most common pattern in atherogenic indices was AIP (94.2%). HbA1c was positively correlated with duration of diabetes (r=0.253, p<0.001). In multivariate logistic regression analysis, duration of diabetes (>10 years) was significantly associated with poor glycemic control with an odds ratio (OR) of 2.31(95% CI; 1.25-4.24, p=0.007). CONCLUSION: The present study indicated that neither the pattern of dyslipidemia nor the atherogenic indices were markers of poor glycemic control among South Indian patients attending our tertiary care institute. However, duration of diabetes was significantly associated with poor glycemic control.

Clinicopathological Profile of Primary Hyperparathyroidism with Special Reference to Ki-67 Labelling Index.

Context: Primary hyperparathyroidism (PHPT) can occur due to a neoplastic process or hyperplasia. While the disease presentation is predominantly asymptomatic in developed countries, this is not the case yet in India. Differentiation of the type of lesion can only be done based on histomorphology but has its own challenges. Immunohistochemical markers like Ki-67 have been studied to aid in diagnosis but data on this is sparse from India. Aims: The aim of this study is to assess the clinical, biochemical and pathological profile of PHPT and to analyse the differences in immunohistochemical marker Ki-67 among the various lesions. Setting and Design: A descriptive study was carried out on 38 PHPT patients who were treated at our institute from January 2011 to March 2021. Materials and Methods: Post-surgery, the causative lesions were categorised as adenoma (31), hyperplasia (5) and carcinoma (2). Clinical, biochemical, radiological and histopathological features of all lesions were collected and analysed. Ki-67 proliferation index was calculated. The various parameters were compared across the three groups of lesions and correlated with Ki-67 index. Results: Out of 38 patients, 37 were symptomatic with skeletal symptoms being the most common followed by renal symptoms. There was no difference in clinical or biochemical parameters among the three types of lesions. Significant negative correlation was seen between serum iPTH and serum 25-OH Vitamin D levels (P0.006) The median Ki-67 index was found to be 0.40% in hyperplasia, 0.49% in adenoma and 5.84% in carcinoma. Conclusion: PHPT still presents as an overtly symptomatic disease in India. Diagnosis of the nature of lesion depends on the accurate application of morphological criteria. A high Ki-67 index was not found to be an absolute marker of carcinoma, as it was also seen in a small proportion of atypical adenomas.

Peroxisome Proliferator-Activated Receptor α and γ Gene Polymorphisms among South Indian Patients with Diabetic Dyslipidaemia.

Background: Peroxisome proliferator-activated receptors (PPAR) α and γ genes play an important role in dyslipidaemia of T2DM. Aims: To estimate the frequency distribution of PPAR α and γ gene polymorphisms in South Indian T2DM patients with dyslipidaemia compared to healthy controls. Normative frequencies of SNPs were established and compared with data for 1000 genome populations. Methods: Eligible 382 cases and 336 age and sex-matched controls were enrolled. Six SNPs in PPARα [rs1800206 C>G (Leu162Val), rs4253778 G>C, rs135542 T>C] and PPARγ [rs3856806 (C>T), rs10865710 (C>G), rs1805192 C>G (Pro12Ala)] genes were selected for genotyping. Results: The allele and gene frequencies did not significantly differ between the diabetic dyslipidaemia cases and healthy controls. However, they were significantly different from that of 1000 genome populations except for rs1800206 C>G (Leu162Val) and rs1805192 C>G (Pro12Ala). Conclusion: The studied polymorphisms in PPARα and PPARγ genes are not associated with diabetic dyslipidaemia among South Indian patients.

Effects of Vitamin D on Migraine: A Meta-Analysis.

Objective: The aim of this study was to evaluate the difference in mean serum 25-hydroxy vitamin D level between migraineurs and nonmigraineurs, the association between hypovitaminosis D and migraine, and the effects of oral vitamin D supplementation on migraine-related symptoms as compared to placebo. Methods: Relevant databases were searched for observational studies and randomized-controlled trials (RCTs) which evaluated the difference in mean serum 25-hydroxy vitamin D level between migraineurs and nonmigraineurs; the association between hypovitaminosis D and migraine; and the effects of vitamin D supplementation on migraine-frequency, duration, and severity. Pooled mean difference and odds ratio were calculated (random-effects model, RevMan version 5.3). Results: Ten observational studies and two RCTs were included. The serum 25-hydroxy vitamin D level in the migraineurs was significantly lower than that in the nonmigraineurs [mean difference - 4.44 ng/mL (95% CI: -6.11, -2.77)] (low-GRADE evidence). Hypovitaminosis D was found to be significantly associated with migraine [OR: 1.95 (95% CI: 1.07, 3.58)] (low-GRADE evidence). As compared to placebo, oral vitamin D supplementation significantly reduced the monthly migraine-frequency [mean difference: -2.20 (95% CI: -3.04, -1.36)]. ,: although it did not reduce the migraine-duration [mean difference: -16.00 hours per month (95% CI: -42.77, 10.76)] and migraine-severity score [standardized mean difference: -0.23 (95% CI: -0.79, 0.32)] (moderate-GRADE evidence). Conclusion: Serum 25-hydroxy vitamin D level was significantly lower in the migraineurs than that in the nonmigraineurs, and hypovitaminosis D was significantly associated with migraine. Oral vitamin D supplementation significantly reduced migraine-frequency, but not its duration and severity.