Effect of Vitamin D analog supplementation on levator ani strength and plasma Vitamin D receptor expression in uterine prolapse patients

Scientific Reports volume 13, Article number: 3616 (2023) Cite this article

957 Accesses

2 Altmetric

Metrics details

Uterine prolapse is a pathological condition that can negatively impact women's quality of life. It is caused by weakening of the pelvic floor muscles. Function of levator ani muscle and other striated muscles is thought to be influenced by Vitamin D levels. Vitamin D exerts its biological effects by adhering to Vitamin D receptors (VDRs) present in striated muscles. We aim to analyze the effect of Vitamin D analog supplementation on levator ani muscle strength in uterine prolapse patients. This was a quasi-experimental study with a pre-post design on 24 postmenopausal women diagnosed with grade III and IV uterine prolapse. Vitamin D levels, VDR, levator ani muscle, and hand grip muscle strength were measured before and after three months of Vitamin D analog supplementation. We found that Vitamin D level, VDR serum level, levator ani muscle strength, and hand grip muscle strength all significantly increase (p < 0.001) following Vitamin D analog supplementation. The correlation coefficient between levator ani muscle and handgrip muscle strength was 0.616 and with p value of 0.001. To conclude, Vitamin D analog supplementation can significantly increase levator ani muscle strength in uterine prolapse patients. We propose that determining Vitamin D level in postmenopausal women and replenishing its deficiency with Vitamin D analog supplementation might aid in preventing POP progression.

Uterine prolapse is one of multiple conditions that fall under the umbrella term of pelvic organ prolapse. It is characterized by descent of the uterus into the vagina due to weakness of endopelvic ligaments, particularly transverse ligaments. Pelvic organ prolapse can present as either vaginal prolapse, uterine prolapse, anterior wall prolapse or cystocele, and posterior wall prolapse or rectocele1,2,3,4.

The reported prevalence of POP varies greatly between studies and is estimated to be anywhere around 3–50%. These substantial differences are attributable to variations in study design, inclusion criteria, and accompanying symptom indicators5. The global prevalence of POP has been reported to be around 9%6. However in low-middle-income countries, this figure is closer to around 15%7.

Risk factors of POP include parity, method of delivery, previous pelvic surgery, BMI, conditions that increase intraabdominal pressure (chronic cough, constipation, heavy manual labor), age, and menopausal status. Prevalence of POP nearly doubles in postmenopausal and older women, with prevalence reaching 36–49% after 60 years of age1,8. While menopause is associated with collagen defects, aging affects POP by causing neuromuscular function and connective tissue changes. Aging is also correlated with gradual weakening of pelvic floor muscle, levator ani, and coccyx striated muscles. It is widely known that anatomical integrity and function of levator ani muscle play a significant role in pelvic organ support9,10. Women with levator ani disorders were found to be at least twice as likely to develop clinically significant POP and to experience recurrence after pelvic surgery11,12.

Unquestionably, the occurrence of POP can affect quality of life (QoL) and harms one's physical, psychological, and social well-being. Pelvic organ prolapse is a particularly complex disorder that involves both physical and functional aspects. Women with POP may experience a range of urinary, gastrointestinal, and sexual symptoms that can seriously impact their QoL and mental health. Overall, women with prolapse had significantly lower QoL than the age-standardized population. The increase in life expectancy and the widespread movement towards improving quality of life have drastically increased the number of women seeking treatment and solutions to their symptoms4,13,14,15,16.Therefore, an effort to increase quality of life and prevent POP progression is continually being searched.

Vitamin D is a fat-soluble secosteroid hormone that regulates calcium, magnesium, and phosphate homeostasis; plays a pivotal role in bone growth; and acts as an antiproliferative and immunomodulatory mediator. In addition, Vitamin D has also been proven to affect muscle strength. Vitamin D exerts its biological effects by adhering to Vitamin D receptors (VDRs) that are also present in striated muscles like levator ani muscle. Through them, Vitamin D can affect striated muscle functions by regulating calcium homeostasis which would affect muscle contractility and help protect muscle cell environment from inflammation1,2,17.

The prevalence of Vitamin D deficiency among postmenopausal women worldwide ranges between 1.6 and 86%. Vitamin D deficiency can be a precipitating factor for pelvic floor damage in postmenopausal women18,19,20. An increase in Vitamin D is predicted to be able to help prevent pelvic organ prolapse progression. This study aims to analyze the effect of Vitamin D analog supplementation on levator ani muscle strength and plasma VDR expression in uterine prolapse patients.

This was a quasi-experimental study with a pre-post design that analyzes the effect of Vitamin D analog supplementation in women with uterine prolapse. We included all postmenopausal women diagnosed with grade III and IV uterine prolapse who came to outpatient clinic of Dr. Hasan Sadikin Bandung from August 2021 to November 2021. Uterine prolapse diagnosis and staging were based on Pelvic Organ Prolapse Quantification (POP-Q) system. Exclusion criteria were as follows:

Patients with comorbidities, such as chronic cough and chronic constipation (these symptoms last for a minimum of 8 weeks).

Patients diagnosed with diseases related to Vitamin D metabolism disorders such as: diabetes mellitus, chronic kidney failure, or malignant diseases

Those who had a history of gastrectomy or jejunoileostomy surgery.

Patients who are currently or have a history of taking cholesterol-lowering drugs (statins and fibrates), anticonvulsants, thiazides, theophylline, orlistat, cimetidine, and Vitamin D supplementation one month prior to this study.

Patients withdrawing from our research.

During the initial presentation, we collected the following data: age, parity, body mass index (BMI), hemoglobin levels, and calcium levels. All subjects were then given 0.5 mcg of Vitamin D analog supplementation for 3 months. We also collected and compared the following data before and after Vitamin D analog supplementation: (1) Vitamin D and VDR serum levels, (2) Levator ani muscle strength, and (3) Hand grip muscle strength. Levator ani muscle strength was measured using perineometer, while handgrip muscle strength was evaluated using hand grip dynamometer.

We tabulated all patients' data on a customized spreadsheet and performed data analysis on Statistical Produce and Service Solutions SPSS software version 25 for Windows (IBM Corp, Armonk, New York, USA). Descriptive statistics were performed as appropriate. Analytical statistics were performed using t test or Wilcoxon test as required, with p < 0.05 considered as significant.

Written informed consent was provided to all study participants prior to engaging in any study-related procedures. Ethical approval of this study was granted by the Health Research Ethics Committee of Hasan Sadikin Hospital, Bandung under the following registration number: LB.02.01/X.6.5/213/2021. This study was conducted according to Declaration of Helsinki. All research procedures were performed in accordance with relevant guidelines and regulations.

We recruited 24 subjects. Most of them were in the age group of 50–70 years old, had parity ≥ 3, and had normal BMI. Mean hemoglobin was 12.82 ± 1.75 and mean calcium level was 4.87 ± 0.42 (Table 1).

We found that levator ani muscle strength significantly increases following Vitamin D analog supplementation (10,00 ± 3,64 to 19,68 ± 3,70, p = 0.001). A similar significant result was also found when testing for handgrip muscle strength after Vitamin D analog supplementation (15,39 ± 3,36 to 23,87 ± 3,81, p = 0.001). Both Vitamin D and VDR serum levels also significantly increase following Vitamin D analog supplementation (both p = 0.001, Table 2). In addition, we also assessed the correlation between levator ani muscle and handgrip muscle strength and found a significant positive correlation (r = 0.616, p = 0.001), indicating that the stronger the levator ani muscle, the stronger the handgrip muscle.

Uterine prolapse is a pathological condition caused by weakening of the pelvic floor muscles. Decreased neuromuscular function and connective tissue changes in older and postmenopausal women are associated with decreased muscle function and therefore uterine prolapse incidence1,2,3,4. There were 24 subjects in this study and most of them were in the age group of 50–70 years old, had parity ≥ 3, and had normal BMI. Age, parity, and BMI are widely known risk factors of POP2,3,4,12.

Aging is the most widely reported contributing factor to pelvic organ prolapse14. As age increases, striated muscle strength becomes weaker and muscle regeneration process grows slower. Furthermore, as people age, their muscle mobility and pelvic supporting tissue integrity decrease8,21,22.

Seven out of 24 subjects had BMI above normal. Excess body mass index is considered a risk factor for uterine prolapse because it correlates with levator ani muscle weakness21,23. A study by Maclennan et al. found that obesity was significantly associated with pelvic floor muscle strength21. Obese women (BMI > 30) have a two-fold risk of experiencing POP compared to those with normal BMI24.

Most of the subjects were multiparous, with parity of ≥ 3. In 2013, Yeniel et al. conducted a study and found that multiparous women had 2.92 times greater risk of developing POP than nulliparous women. This same study also found that the risk of POP in each subsequent delivery increased by 1.2 times25. In addition, another study in 2017 stated that vaginal delivery was associated with worse pelvic organ support five years following first delivery26.

All subjects in this study had Vitamin D deficiency since the beginning of the study. Our findings are in line with previous studies on Vitamin D levels in postmenopausal women. According to a study conducted in China, the incidence of Vitamin D deficiency among postmenopausal women is approximately 99.4 percent. A study conducted in Bandung and Sumedang, Indonesia, revealed that 94.3% of postmenopausal women lacked Vitamin D19,20,27.

A vast body of evidence suggests that abnormalities of Vitamin D level and its signaling may play a significant role in the development of obstetric and gynecological disorders in various age periods of a woman's life. Vitamin D level abnormalities have been linked to diseases like PCOS, endometriosis, ovarian cancer, breast cancer, infertility, and pelvic organ prolapse, especially in postmenopausal women28. The link between Vitamin D abnormalities and pelvic organ prolapse development lies in Vitamin D's function on striated muscles. Previous studies have extensively documented the effects of Vitamin D on the strength and function of striated muscle. Improved physical performance has been linked to Vitamin D. Conversely, muscle weakness and sarcopenia are associated with Vitamin D deficiency. Pelvic floor muscle weakness can manifest clinically as pelvic floor dysfunction symptoms. Levator ani and coccygeus muscles are important components of the pelvic floor and can be affected by Vitamin D status19,20,29,30. Our results indicated that Vitamin D deficiency could be one precipitating factor for pelvic floor damage in postmenopausal women20,21,22. This is supported by previous studies in America, Canada, and Europe which showed that Vitamin D deficiency is an important factor in POP occurrence31.

In this study, levator ani muscle contraction strength before Vitamin D analog supplementation was 10.00 ± 3.64 cmH2O with a range of 4.70–17.00. After Vitamin D analog supplementation, levator ani muscle contraction strength increased significantly to 19.68 ± 3.70 cmH2O with a range of 10.70–25.60 (p = 0.001). Pelvic organ prolapse can be treated both medically and surgically. Pessaries, pelvic floor muscle training, or both can be used as non-invasive treatments to help alleviate POP symptoms. The goal of pelvic muscle training is to strengthen pelvic floor muscle (including levator ani) and help improve POP symptoms, particularly urinary incontinence. One previous study mentioned that pelvic floor muscle training guided by a motion-based digital therapy device can significantly improve urinary incontinence and decrease its episodes32. The result of our study suggested that Vitamin D analog supplementation can strengthen levator ani muscle contraction and thus aid in improving POP symptoms and preventing its progression.

We also found a significant increase in hand grip muscle strength following three months of Vitamin D analog supplementation (p = 0.001). Prior to supplementation, mean hand grip muscle strength was 15.39 ± 3.36 (range = 10.00–21.00), then after supplementation, hand grip muscle strength increased to 23.87 ± 3.81 (range = 16.70–30.40). A study conducted by Setiati et al., reported a similar result to our study, where alfacalcidol (Vitamin D analog) was found to increase hand grip muscle strength in elderly. The hand grip strength correlates with total muscle strength and can be used to assess an individual's overall muscle strength30. Furthermore, we also found a positive correlation between levator ani muscle and handgrip muscle strength meaning that the stronger the levator ani muscle, the stronger the handgrip muscle.

Ceglia et al. reported that Vitamin D may affect striated muscle through both genomic and nongenomic mechanisms. In the genomic pathway, Vitamin D regulates gene transcription by binding to Vitamin D receptors on the nuclear membrane of muscle cells, resulting in the differentiation and proliferation of muscle cells through the effects of insulin growth factor (IGF), which eventually induces muscle hypertrophy. Whereas in the nongenomic pathway, Vitamin D (1,25(OH)D) binds to receptor membrane which then activates signal transduction, triggering the MAP Kinase (MAPK) and Phospholipase C (PLC) pathways, and causing a rapid influx of calcium into cells and affecting muscle cell contraction33.

In conclusion, Vitamin D analog supplementation can significantly increase levator ani muscle strength. We propose that determining Vitamin D level in postmenopausal women and replenishing its deficiency with Vitamin D analog supplementation might help strengthen pelvic floor muscle and therefore aid in preventing POP progression.

This is a preliminary study that analyzes the effect of Vitamin D supplementation towards pelvic floor muscle strength, particularly levator ani muscle strength. Further clinical studies on the effect of Vitamin D supplementation towards rate of recurrence and risk of surgery are needed. In addition, future studies should also look at the dosage of Vitamin D supplementation needed based on prolapse severity.

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Navaneethan, P. R., Kekre, A., Jacob, K. S. & Varghese, L. Vitamin D deficiency in postmenopausal women with pelvic floor disorders. J. Midlife Health 6(2), 66 (2015).

PubMed PubMed Central Google Scholar

Giarenis, I. & Robinson, D. Prevention and management of pelvic organ prolapse. F1000Prime Rep. 6 (2014).

Kusuma, I. G. Y. S., Putra, I. G. M., Megadhana, I. W., Sanjaya, I. N. H. & Manuaba, I. F. Characteristic of patients with pelvic organ prolapse in obstetric and gynecologic outpatient clinic in Sanglah Hospital, Bali, Indonesia from January 2014 to December 2015. Bali Med. J. 6(1), 76 (2017).

Article Google Scholar

Sayko, S. K., Kurniawati, E. M. & Lestari, P. Age as the risk factor that affected the increased degree of uterine prolapse. Biomol. Heal. Sci. J. Universitas Airlangga 1(1), 20–24 (2018).

Article Google Scholar

Weintraub, A. Y., Glinter, H. & Marcus-Braun, N. Narrative review of the epidemiology, diagnosis and pathophysiology of pelvic organ prolapse. Int. Braz. J. Urol. 46(1), 5–14 (2020).

Article PubMed PubMed Central Google Scholar

Masenga, G. G., Shayo, B. C. & Rasch, V. Prevalence and risk factors for pelvic organ prolapse in Kilimanjaro, Tanzania: A population based study in Tanzanian rural community. PLoS ONE 13(4), e0195910. https://doi.org/10.1371/journal.pone.0195910 (2018).

Article CAS PubMed PubMed Central Google Scholar

Friedman, T., Eslick, G. D. & Dietz, H. P. Risk factors for prolapse recurrence: Systematic review and meta-analysis. Int. Urogynecol. J. 29(1), 13–21 (2018).

Article PubMed Google Scholar

Vergeldt, T. F. M., Weemhoff, M., IntHout, J. & Kluivers, K. B. Risk factors for pelvic organ prolapse and its recurrence: A systematic review. Int. Urogynecol. J. 26(11), 1559–1573 (2015).

Article PubMed PubMed Central Google Scholar

Tinelli, A. et al. Age-related pelvic floor modifications and prolapse risk factors in postmenopausal women. Menopause 17(1), 204–212 (2010).

Article PubMed Google Scholar

DeLancey, J. The appearance of levator ani muscle abnormalities in magnetic resonance images after vaginal delivery. Obstet. Gynecol. 101(1), 46–53 (2003).

PubMed PubMed Central Google Scholar

Yeung, E., Malacova, E. & Maher, C. Is levator ani avulsion a risk factor for prolapse recurrence? A systematic review and meta-analysis. Int. Urogynecol. J. 33(7), 1813–1826 (2022).

Article PubMed PubMed Central Google Scholar

Nyhus, M. Ø., Mathew, S., Salvesen, K. Å. & Volløyhaug, I. The impact of levator ani muscle trauma and contraction on recurrence after prolapse surgery. Int. Urogynecol. J. 33(10), 2879–2885. https://doi.org/10.1007/s00192-022-05168-8 (2022).

Article CAS PubMed PubMed Central Google Scholar

Yuk, J. S., Lee, J. H., Hur, J. Y. & Shin, J. H. The prevalence and treatment pattern of clinically diagnosed pelvic organ prolapse: A Korean National Health insurance database-based cross-sectional study 2009–2015. Sci. Rep. 8(1), 1–6 (2018).

Article Google Scholar

Wang, B. et al. Global burden and trends of pelvic organ prolapse associated with aging women: An observational trend study from 1990 to 2019. Front. Public Heal. 15, 10. https://doi.org/10.3389/fpubh.2022.975829/full (2022).

Article Google Scholar

Laganà, A. S., La Rosa, V. L., Rapisarda, A. M. C. & Vitale, S. G. Pelvic organ prolapse: The impact on quality of life and psychological well-being. J Psychosom. Obstet. Gynecol. 39(2), 164–166. https://doi.org/10.1080/0167482X.2017.1294155 (2018).

Article Google Scholar

Vitale, S. G., La Rosa, V. L., Rapisarda, A. M. C. & Laganà, A. S. Sexual life in women with stress urinary incontinence. Oman Med. J. 32(2), 174–175 (2017).

Article PubMed PubMed Central Google Scholar

Kusumawati, S., Purwara, B., Sasotya, R. M. & Sari, D. Korelasi kekuatan kontraksi otot gastrocnemius soleus dengan otot levator ani penderita prolapsus uteri (Universitas Padjadjaran, 2016).

Google Scholar

Kweder, H. & Eidi, H. Vitamin D deficiency in elderly: Risk factors and drugs impact on Vitamin D status. Avicenna J. Med. 8(04), 139–146 (2018).

Article PubMed PubMed Central Google Scholar

Aydogmus, S. et al. Association of antepartum Vitamin D levels with postpartum pelvic floor muscle strength and symptoms. Int. Urogynecol. J. Pelvic Floor Dysfunct. 26(8), 1179–1184 (2015).

Article CAS Google Scholar

Chiang, C. M., Ismaeel, A., Griffis, R. B. & Weems, S. Effects of Vitamin D supplementation on muscle strength in athletes: A systematic review. J. Strength Cond. Res. 31(2), 566–574 (2017).

Article PubMed Google Scholar

MacLennan, A. H., Taylor, A. W., Wilson, D. H. & Wilson, D. The prevalence of pelvic floor disorders and their relationship to gender, age, parity and mode of delivery. BJOG 107(12), 1460–1470 (2000).

Article CAS PubMed Google Scholar

Kinman, C. L. et al. The relationship between age and pelvic organ prolapse bother. Int. Urogynecol. J. 28(5), 751–755 (2017).

Article PubMed Google Scholar

Giri, A., Hartmann, K. E., Hellwege, J. N., Velez Edwards, D. R. & Edwards, T. L. Obesity and pelvic organ prolapse: A systematic review and meta-analysis of observational studies. Am. J. Obstet. Gynecol. 217(1), 11-26.e3 (2017).

Article PubMed Google Scholar

Rogers, R. & Fashokun, T. Pelvic organ prolapse in females: Epidemiology, risk factors, clinical manifestations, and management. UpToDate. (2021).

Yeniel, A. Ö., Ergenoglu, A. M., Askar, N., Itil, I. M. & Meseri, R. How do delivery mode and parity affect pelvic organ prolapse?. Acta Obstet. Gynecol. Scand. 92(7), 847–851 (2013).

Article PubMed Google Scholar

Handa, V. L., Blomquist, J. L., Roem, J. & Muňoz, A. Longitudinal study of quantitative changes in pelvic organ support among parous women. Am. J. Obstet. Gynecol. 218(3), 320.e1-320.e7 (2018).

Article PubMed Google Scholar

Berek, J. S. & Deborah, B. L. Berek & Novak's Gynecology 16th edn. (Wolters Kluwer, Philadelphia, 2020).

Google Scholar

Colonese, F. et al. The pleiotropic effects of Vitamin D in gynaecological and obstetric diseases: An overview on a hot topic. Biomed. Res. Int. 2015, 986281 (2015).

Article PubMed PubMed Central Google Scholar

Biben, V., Defi, I. R., Nugraha, G. I. & Setiabudiawan, B. Vitamin D status and its impact on body composition in elderly community-dwelling individuals in Bandung and Sumedang, West Java province, Indonesia. Asian J. Epidemiol. 10(2), 63–69 (2017).

Article Google Scholar

Setiati, S., Fransiska, J. E., Tamin, T. Z. & Istanti, R. Combination of alfacalcidol and calcium improved handgrip strength and mobility among Indonesian older women: A randomized controlled trial. Geriatr. Gerontol. Int. 18(3), 434–440 (2018).

Article PubMed Google Scholar

Parker-Autry, C. Y., Burgio, K. L. & Richter, H. E. Vitamin D status: A review with implications for the pelvic floor. Int. Urogynecol. J. 23(11), 1517–1526 (2012).

Article PubMed PubMed Central Google Scholar

Weinstein, M. M., Dunivan, G., Guaderrama, N. M. & Richter, H. E. Digital therapeutic device for urinary incontinence. Obstet. Gynecol. 139(4), 606–615. https://doi.org/10.1097/AOG.0000000000004725 (2022).

Article CAS PubMed PubMed Central Google Scholar

Ceglia, L. & Harris, S. S. Vitamin D and its role in skeletal muscle. Calcif. Tissue Int. 92(2), 151–162 (2013).

Article CAS PubMed Google Scholar

Download references

Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Padjadjaran – Dr. Hasan Sadikin Hospital, Jl. Pasteur 38, Bandung, 40161, West Java, Indonesia

Andi Kurniadi, Asri Kurnia Dewi, R. M. Sonny Sasotya, Benny Hasan Purwara & Jessica Kireina

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

A.K., A.K.D., R.M.S.S. conceptualized and designed the study, collected the data, performed the analysis, and composed the manuscript B.H.P. designed the study, composed, and revised the manuscript. J.K. composed and revised the manuscript. All authors reviewed the manuscript.

Correspondence to Andi Kurniadi.

The authors declare no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

Kurniadi, A., Dewi, A.K., Sasotya, R.M.S. et al. Effect of Vitamin D analog supplementation on levator ani strength and plasma Vitamin D receptor expression in uterine prolapse patients. Sci Rep 13, 3616 (2023). https://doi.org/10.1038/s41598-023-30842-2

Download citation

Received: 25 August 2022

Accepted: 02 March 2023

Published: 03 March 2023

DOI: https://doi.org/10.1038/s41598-023-30842-2

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.