Zhaojun Mei1
Dandan Li- 1Luzhou Maternal and Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, China
- 2Department of Gynaecology, Luzhou Maternal and Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, China
- 3Department of Nephrology, Luzhou Maternal and Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, China
- 4School of Basic Medical Sciences, University of Chinese Academy of Sciences, Beijing, China
Vitamin D (VD) is known to play an important role in the maintenance of calcium homeostasis and bone metabolism. In recent years, there has also been a growing interest in Vitamin D for health issues beyond the bones. Menopausal women are at risk of reduced bone density and increased risk of fracture due to a decline in estrogen levels. There is also an increased risk of cardiovascular disease, diabetes and hyperlipidaemia due to impaired lipid metabolism. The menopausal and emotional symptoms due to menopause are also increasingly prominent. This article summarizes the role of Vitamin D in menopausal women’s health, including the effects of Vitamin D on skeletal muscle, cardiovascular disease, Genitourinary Syndrome of Menopause (GSM), cancer and emotional symptoms. Vitamin D regulates the growth of vaginal epithelial cells and alleviates genitourinary tract problems in menopausal women. Vitamin D also modulates immune function and influences the production of adipokines. Vitamin D and its metabolites also have an anti-proliferative effect on tumour cells. This narrative review, by summarizing recent work on the role of Vitamin D in menopausal women and in animal models of menopause, aims to provide a basis for further development of the role of Vitamin D in the health of menopausal women.
1 Introduction
As the population ages, the problems associated with menopause in women become more pronounced (Mosconi et al., 2021). As a result of ovarian failure, estrogen declines in menopausal women, leading to short-term menstrual disorders, hot flushes and night sweats, sleep disturbances, and loss of libido, and long-term increased risk of osteoporosis and cardiovascular disease (Matyjaszek-Matuszek et al., 2015). Estrogen therapy is an important option for menopausal women. There is still much debate about the long-term use of estrogen in menopausal women, especially in those at high risk of developing breast cancer, endometrial cancer and cardiovascular disease (Sturdee et al., 2011). Therefore, non-hormone replacement therapy is of increasing concern.
VD is a fat-soluble vitamin that includes VD2 and VD3. VD2 is of plant origin. VD3 is synthesised from 7-dehydrocholesterol in human skin by sunlight exposure and is converted to the biologically active 1,25(OH)2D3 by the action of liver, kidney and mitochondrial hydroxylases (Vacek et al., 2012). VD mainly regulates calcium and phosphorus metabolism and promotes bone growth. There is growing interest in the important role of VD outside the skeleton, including regulation of immune function, regulation of cell growth, and reduction of oxidative stress and tissue damage (Matta Reddy et al., 2022). Studies have linked VD deficiency to cardiovascular disease, metabolic syndrome, cancer and immune system disorders (Sutton and MacDonald, 2003; Rosen, 2011). The Institute of Medicine (IOM) considered a 25(OH)D level below 20 ng/mL to be considered VD deficiency. However, there is no agreement between institutions on the ideal 25(OH)D level. The Endocrine Society defined 25(OH)D concentrations of 30 ng/mL as the lower limit of normal, and 21–29 ng/mL as inadequate and <20 ng/mL as deficient. About one billion people worldwide are VD deficient (Holick, 2007). It is worth noting that VD deficiency is widely prevalent among menopausal women, accounting for about 50%–80% of the total number of menopausal women. (Kennel et al., 2010; Samuel and Borrell, 2013). In menopausal women, the ability of the skin and kidneys to produce 1,25(OH)2D3 is reduced and intestinal absorption is reduced, further contributing to lower VD levels in the body (Holick et al., 1989). In this review, we review the literature published in recent years on the role of VD in osteoporosis, cardiovascular disease and oncology in menopausal women, including randomized controlled trials, observational studies and animal studies, to summarise the potential role of VD in improving menopausal symptoms and related health outcomes.
2 Osteoporosis and muscle loss
The incidence of osteoporosis gradually increases with age. In menopausal women, due to a decrease in estrogen production, calcium absorption in the small intestine is reduced, ultimately leading to a decrease in bone density (de Lemos, 2004). The most important functions of VD are to promote the absorption of calcium and phosphorus from the small intestine, to promote new bone production and calcification, and to regulate parathyroid hormone to maintain blood calcium and phosphorus concentrations (Fleet, 2022). It plays a role in the prevention or treatment of osteoporosis. When VD levels are reduced, this leads to secondary hyperparathyroidism, which induces a series of changes in bone metabolism leading to reduced bone mass and osteoporotic fractures (Mosali et al., 2014). VD receptors (VDR) have been shown to be present in muscle tissue, and VD is involved in regulating the proliferation and differentiation of myoblasts, significantly improving muscle strength and function, and improving balance (Dzik and Kaczor, 2019). Myalgia, decreased muscle strength, reduced physical performance, and altered muscle morphology are common in patients with VD deficiency. A study assessed the relationship between muscle function and muscle strength in 54 postmenopausal women and found that 25(OH)D levels ≥20 ng/mL were associated with better lower limb muscle function and strength (Mastaglia et al., 2011). Calcium plus VD has been shown to reduce bone loss in perimenopausal and postmenopausal women. In an 18-year study of 72,337 postmenopausal women (Feskanich et al., 2003), adequate VD intake was found to be associated with a reduced risk of osteoporotic hip fracture in postmenopausal women. A meta-analysis demonstrated that combined calcium and VD supplementation may prevent osteoporotic hip fractures in postmenopausal women (Liu et al., 2020). VD, a calcium-regulating hormone that affects bone metabolism and calcium homeostasis, is a commonly used drug for the prevention and treatment of osteoporosis. There is considerable controversy regarding the dose of VD for the prevention and treatment of osteoporosis, and more studies should be conducted to explore the optimal dose of VD for different populations. As shown in Table 1, we summarise the effects of VD on osteoporosis and muscle loss.
TABLE 1. Studies of VD in osteoporosis and muscle loss.
3 Cardiovascular disease and glucolipid metabolism
Estrogen has a protective effect on the heart. It regulates lipid metabolism in the liver and increases the synthesis of low-density lipoprotein (LDL) receptors, thereby reducing LDL levels. Estrogen also increases the activity of lipoprotein lipase and increases high-density lipoprotein (HDL) levels (Mendelsohn and Karas, 1999). Menopause is associated with weight gain and changes in body fat distribution in women. Menopausal women suffer from lower levels of estrogen, leading to disorders of lipid metabolism and abnormal fat distribution in the body (Usategui-Martín et al., 2019). The dysregulation of lipid metabolism further leads to the development of metabolic syndromes (MetS) including cardiovascular disease, type II diabetes, and hyperlipidaemia (Janssen et al., 2002). Pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) and adipocytokines play an important role in hepatic steatosis and inflammatory responses. In recent years, there has been an increasing number of studies on the effects of VD on non-classical pathways, such as VD may prevent the development of diabetes, hyperlipidaemia and cardiovascular disease (Darraj et al., 2019). VD regulates immune function and has a variety of biological effects such as anti-inflammatory and anti-oxidative stress (Lee et al., 2015). There is growing evidence that VD deficiency may lead to immune dysfunction and promote the development of cardiovascular and metabolic diseases (Martins et al., 2007; Pacini et al., 2008). A cross-sectional study found that 25(OH)D was inversely associated with fasting glucose (Alharazy et al., 2021), insulin and C-peptide in postmenopausal women with type II diabetes. VDR is expressed in the cardiovascular system, and VD inhibits the renin-angiotensin system, increases endothelial-type nitric oxide and avoids atherosclerosis (Li et al., 2002). VD regulates insulin secretion and enhances insulin sensitivity, reduces systemic inflammation thereby improving insulin resistance (Rammos et al., 2008). Cardiomyocytes have VDR and 1,25(OH)2D3-dependent calcium-binding proteins. VD has an effect on extracellular matrix remodelling, cardiomyocyte hypertrophy and proliferation (Zittermann et al., 2003). VD can also influence the production of adipokines (Rodrigues et al., 2014). Ma et al. found that serum 25(OH) D was independently and negatively associated with carotid atherosclerosis in postmenopausal women with normal blood pressure and glucose tolerance (Ma et al., 2014). Chacko et al. demonstrated that higher serum 25(OH) D concentrations may be negatively associated with obesity, triglycerides, HDL-cholesterol ratio and metabolic syndrome (Chacko et al., 2011). A cohort study found that VD deficiency in postmenopausal women was associated with a higher prevalence of MetS (Schmitt et al., 2018). Women with VD deficiency had a higher risk of MetS and LDL than those with adequate levels. There is still considerable controversy about VD attenuating cardiovascular disease in menopausal women, and some studies have reported no association between serum VD levels and MetS (de Boer et al., 2008; Guasch et al., 2012). VD deficiency is very common in menopausal women and this undoubtedly exacerbates the risk of menopause-related cardiovascular disease and dyslipidaemia. Therefore, the addition of VD to conventional therapy may be a promising treatment modality. As shown in Table 2, we summarise the studies related to VD on cardiovascular disease and abnormal glucolipid metabolism.
TABLE 2. Studies on the role of VD in metabolic syndrome.
4 Genitourinary Syndrome of Menopause
Genitourinary syndrome of menopause (GSM) is a condition in which a woman experiences vaginal dryness, pain, difficulty with intercourse, recurrent vaginitis and difficulty urinating, along with frequent and urgent urination, when her ovarian function declines and her estrogen levels decrease (Mei and Li, 2022). Reduced estrogen further leads to atrophy of the vaginal wall, thinning of the epithelium, reduced glycogen content, increased pH in the vagina and increased bacterial vaginosis infections (Navaneethan et al., 2015). Estrogen therapy is one way to improve the symptoms of vaginal atrophy in post-menopausal women. However, major concerns remain about the use of estrogen in patients with breast and endometrial cancers. Vaginal atrophy is one of the most common side effects of tamoxifen use in breast cancer patients. The use of hormones for vaginal atrophy is prohibited in these women. Therefore there is a growing interest in finding safe and effective alternatives. VD is involved in regulating cell growth and differentiation (Costantino and Guaraldi, 2008), particularly in the vaginal epithelium. VD supplementation will promote squamous maturation of the vaginal epithelium, proliferation and differentiation of vaginal mucosal cells and re-establishment of the physical barrier of the vagina. Rad et al. demonstrated that VD vaginal suppositories improved vaginal dryness and lowered pH in women with vaginal atrophy (Rad et al., 2015). A double-blind placebo-controlled trial found that 40,000 IU of VD given weekly to 80 postmenopausal women significantly improved vaginal maturation index (VMI), vaginal pH and vaginal dryness symptoms (Kamronrithisorn et al., 2020). Recurrent urinary tract infections are another problem faced by postmenopausal women. Tight junction proteins play an important function in maintaining the integrity of the epithelial barrier. When estrogen levels decrease, accompanied by a decrease in antimicrobial peptides and barrier proteins, the permeability of the bladder urinary epithelium increases, further leading to thinning of the urinary epithelium and increasing the risk of urinary tract infections. Mohanty et al. found that VD induced ocludin and claudin-14 in bladder maturation surface cells (Mohanty et al., 2020), which increased intercellular adhesion and promoted epithelial integrity. A possible mechanism for the vaginal effects of VD is due to the presence of VDR in the basal cell layer of vaginal tissue (Keshavarzi et al., 2019). Lee et al. first revealed that VD positively regulates intercellular junctions by increasing the VDR/p-RhoA/p-Ezrin pathway (Lee et al., 2017). VD has a protective effect against vaginal atrophy in postmenopausal women and is inexpensive and without adverse effects. Therefore, in addition to topical oestrogen use, oral or vaginal VD use in post-menopausal women is very effective in reducing GSM-induced menopausal symptoms.
5 Cancer
The immune microenvironment has an important impact on the inflammatory status of postmenopausal women. Estrogen acts as a booster of humoral immunity and, due to the lack of estrogen in postmenopausal women, their levels of the pro-inflammatory cytokines TNF-α, IL-1 and IL-6 are elevated against pathogens (Gameiro and Romao, 2010). Human papillomavirus (HPV) infection has a second peak in postmenopausal women (Smith et al., 2008), and the vast majority (over 95%) of cervical cancers are caused by HPV. VD and its metabolites have anti-proliferative effects on tumour cells, further inhibiting tumour spread and invasion by inhibiting tumour angiogenesis and cell growth, thereby reducing the incidence of many cancers (Vanoirbeek et al., 2011). Moreover, VD can also increase the sensitivity of radiotherapy and chemotherapy (Pilz et al., 2013). It is well known that immune cells express VDR. VD activates and induces the expression of VDR in lymphocytes, while dendritic cells and macrophages constitutively express the receptor (Martens et al., 2020). Higher VD intake is associated with a reduced risk of lung, breast and ovarian cancers (Cheng et al., 2013). 1,25(OH)2D3 binds to the VDR to promote immunomodulatory and anticancer effects. Serum 25(OH) D levels were found to be significantly lower in breast cancer patients than in healthy controls (Karthikayan et al., 2018). A meta-analysis of 14 studies showed a significant negative association between serum 25(OH)D levels and breast cancer risk (RR = 0.845, 95% CI = 0.750–0.951) (Wang et al., 2013). A dose-response analysis showed a significant 3.2% reduction in breast cancer risk for every 10 ng/mL increase in serum 25(OH)D concentrations (Abbas et al., 2008). A population-based case-control study found a significant negative association between serum 25(OH)D concentrations and postmenopausal breast cancer risk. In the Women’s Health Initiative calcium + VD (CaD) trial, CaD supplementation in postmenopausal women was found to be associated with a reduced risk of breast ductal carcinoma in situ (Peila et al., 2021). The study further found that VD intake in non-smoking postmenopausal women was associated with a lower risk of lung cancer. Cadeau et al. evaluated the interaction between VD supplementation and menopausal hormone therapy (MHT) use during menopausa (Cadeau et al., 2016). A prospective survey of VD supplementation in 57,403 postmenopausal women found that VD supplementation may reduce the risk of breast cancer in MHT users. Serum VD levels are also associated with the presence and histologic grade of colorectal adenomas in perimenopausal and postmenopausal women. Most current studies suggest that adequate VD supplementation in perimenopausal and postmenopausal women may be beneficial in reducing cancer risk.
6 Climacteric and emotional symptoms
The majority of women in the ageing population spend 1/3 of their lives in a post-menopausal state, and menopausal women are significantly more likely to suffer from depression and anxiety disorders due to loss of ovarian function and low estrogen status (Arevalo et al., 2015). However, women going through menopause can experience a range of vasodilatory symptoms in the short and medium term, including: hot flushes, palpitations, night sweats, and cold hands and feet (Castanho et al., 2014). Studies have demonstrated that the status of pro-inflammatory cytokines may be higher in the periphery and hippocampus of depressed patients, and that pro-inflammatory cytokines can induce depression-like behaviours (Jeon and Kim, 2017). There is growing interest in the potential of nutrients to improve mental health and mental status in women. People with depression are usually less physically active and will spend more time indoors. VDR is located in brain regions involved in emotional processing (Lerchbaum, 2014). VD levels are low in depressed patients and supplementation has been shown to help improve mood. VD influences the production of pro-inflammatory cytokines, which in turn influence mood by activating the stress response (Kerr et al., 2015). If the central nervous system is involved, cognitive function may be affected. Annweiler et al (Annweiler et al., 2010) demonstrated that VD insufficiency is associated with cognitive impairment. VD has a protective and regulatory effect on the brain dopamine system, suggesting similarity to antidepressants. Zhang et al. evaluated the effects of VD and 17β-estradiol on depressive symptoms in ovarian-deviated rats (OVX) (Zhang et al., 2020). It was found that both VD and 17β-estradiol showed antidepressant-like activity in OVX rats, and exerted neuroprotective effects by reducing OVX-induced apoptosis and neuronal damage, and reducing the expression of pro-inflammatory cytokines in the hippocampus of OVX rats. A study of 81,189 members of the Women’s Health Initiative found that 400 IU of VD from food sources reduced the risk of depressive symptoms in year 3 by 20% compared to 100 IU from food sources (OR: 0.80; 95% ci: 0.67, 0.95; p = 0.001) (Bertone-Johnson et al., 2011). In addition to this, there is an association between VD deficiency and pelvic organ prolapse (POP) and stress urinary incontinence in postmenopausal women. In a prospective case-control study, VD levels were significantly lower in women with POP than in women without POP (Navaneethan et al., 2015).
7 Conclusion
In summary, VD insufficiency is a common but neglected health problem in healthy menopausal women. VD status is associated with skeletal muscle, cardiovascular disease, diabetes, GSM, and menopausal symptoms in menopausal women. VD supplementation is a safe, inexpensive treatment that plays an important role in improving the overall state of menopausal women. Therefore, it is necessary to study the effects of VD supplementation in perimenopausal and postmenopausal women. In the future, more high-quality randomised controlled trials are needed to determine optimal 25(OH)D levels and to clarify the potential adverse effects of VD and calcium supplementation.
Author contributions
ZM and DL organized the manuscript, HH and YZ revised the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Abbas, S., Linseisen, J., Slanger, T., Kropp, S., Mutschelknauss, E. J., Flesch-Janys, D., et al. (2008). Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer-results of a large case-control study. Carcinogenesis 29 (1), 93–99. doi:10.1093/carcin/bgm240
Alharazy, S., Alissa, E., Lanham-New, S., Naseer, M. I., Chaudhary, A. G., and Robertson, M. D. (2021). Association between vitamin D and glycaemic parameters in a multi-ethnic cohort of postmenopausal women with type 2 diabetes in Saudi Arabia. BMC Endocr. Disord. 21 (1), 162. doi:10.1186/s12902-021-00825-3
Annweiler, C., Schott, A. M., Allali, G., Bridenbaugh, S. A., Kressig, R. W., Allain, P., et al. (2010). Association of vitamin D deficiency with cognitive impairment in older women: Cross-sectional study. Neurology 74(1), 17–29. doi:10.1212/WNL.0b013e3181beecd3
Arevalo, M. A., Azcoitia, I., and Garcia-Segura, L. M. (2015). The neuroprotective actions of oestradiol and oestrogen receptors. Nat. Rev. Neurosci. 16(1), 17–29. doi:10.1038/nrn3856
Bertone-Johnson, E. R., Powers, S. I., Spangler, L., Brunner, R. L., Michael, Y. L., Larson, J. C., et al. (2011). Vitamin D intake from foods and supplements and depressive symptoms in a diverse population of older women. Am. J. Clin. Nutr. 94 (4), 1104–1112. doi:10.3945/ajcn.111.017384
Cadeau, C., Fournier, A., Mesrine, S., Clavel-Chapelon, F., Fagherazzi, G., and Boutron-Ruault, M. C. (2016). Postmenopausal breast cancer risk and interactions between body mass index, menopausal hormone therapy use, and vitamin D supplementation: Evidence from the E3N cohort. Int. J. Cancer 139 (10), 2193–2200. doi:10.1002/ijc.30282
Cangussu, L. M., Nahas-Neto, J., Orsatti, C. L., Poloni, P. F., Schmitt, E. B., Almeida-Filho, B., et al. (2016). Effect of isolated vitamin D supplementation on the rate of falls and postural balance in postmenopausal women fallers: A randomized, double-blind, placebo-controlled trial. Menopause 23 (3), 267–274. doi:10.1097/gme.0000000000000525
Castanho, T. C., Moreira, P. S., Portugal-Nunes, C., Novais, A., Costa, P. S., Palha, J. A., et al. (2014). The role of sex and sex-related hormones in cognition, mood and well-being in older men and women. Biol. Psychol. 103, 158–166. doi:10.1016/j.biopsycho.2014.08.015
Chacko, S. A., Song, Y., Manson, J. E., Van Horn, L., Eaton, C., Martin, L. W., et al. (2011). Serum 25-hydroxyvitamin D concentrations in relation to cardiometabolic risk factors and metabolic syndrome in postmenopausal women. Am. J. Clin. Nutr. 94 (1), 209–217. doi:10.3945/ajcn.110.010272
Cheng, Q., Wu, X., Du, Y., Hong, W., Tang, W., Li, H., et al. (2018). Levels of serum sclerostin, FGF-23, and intact parathyroid hormone in postmenopausal women treated with calcitriol. Clin. Interv. Aging 13, 2367–2374. doi:10.2147/cia.S186199
Cheng, T. Y., Lacroix, A. Z., Beresford, S. A., Goodman, G. E., Thornquist, M. D., Zheng, Y., et al. (2013). Vitamin D intake and lung cancer risk in the Women's Health Initiative. Am. J. Clin. Nutr. 98 (4), 1002–1011. doi:10.3945/ajcn.112.055905
Costantino, D., and Guaraldi, C. (2008). Effectiveness and safety of vaginal suppositories for the treatment of the vaginal atrophy in postmenopausal women: An open, non-controlled clinical trial. Eur. Rev. Med. Pharmacol. Sci. 12 (6), 411–416.
Darraj, H., Badedi, M., Poore, K. R., Hummadi, A., Khawaji, A., Solan, Y., et al. (2019). Vitamin D deficiency and glycemic control among patients with type 2 diabetes mellitus in Jazan City, Saudi Arabia. Diabetes Metab. Syndr. Obes. 12, 853–862. doi:10.2147/dmso.S203700
de Boer, I. H., Tinker, L. F., Connelly, S., Curb, J. D., Howard, B. V., Kestenbaum, B., et al. (2008). Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women's Health Initiative. Diabetes Care 31 (4), 701–707. doi:10.2337/dc07-1829
de Lemos, M. L. (2004). Seeking clarification of osteoporosis guidelines. Cmaj 171 (9), 1022–1023. doi:10.1503/cmaj.1040953
Dzik, K. P., and Kaczor, J. J. (2019). Mechanisms of vitamin D on skeletal muscle function: Oxidative stress, energy metabolism and anabolic state. Eur. J. Appl. Physiol. 119 (4), 825–839. doi:10.1007/s00421-019-04104-x
Ferreira, P. P., Cangussu, L., Bueloni-Dias, F. N., Orsatti, C. L., Schmitt, E. B., Nahas-Neto, J., et al. (2020). Vitamin D supplementation improves the metabolic syndrome risk profile in postmenopausal women. Climacteric 23 (1), 24–31. doi:10.1080/13697137.2019.1611761
Feskanich, D., Willett, W. C., and Colditz, G. A. (2003). Calcium, vitamin D, milk consumption, and hip fractures: A prospective study among postmenopausal women. Am. J. Clin. Nutr. 77 (2), 504–511. doi:10.1093/ajcn/77.2.504
Fleet, J. C. (2022). Vitamin D-mediated regulation of intestinal calcium absorption. Nutrients 14 (16), 3351. doi:10.3390/nu14163351
Gameiro, C., and Romao, F. (2010). Changes in the immune system during menopause and aging. Front. Biosci. (Elite Ed. 2 (4), 1299–1303. doi:10.2741/e190
Gao, L. H., Zhu, W. J., Liu, Y. J., Gu, J. M., Zhang, Z. L., Wang, O., et al. (2015). Physical performance and life quality in postmenopausal women supplemented with vitamin D: A two-year prospective study. Acta Pharmacol. Sin. 36 (9), 1065–1073. doi:10.1038/aps.2015.55
Guasch, A., Bulló, M., Rabassa, A., Bonada, A., Del Castillo, D., Sabench, F., et al. (2012). Plasma vitamin D and parathormone are associated with obesity and atherogenic dyslipidemia: A cross-sectional study. Cardiovasc Diabetol. 11, 149. doi:10.1186/1475-2840-11-149
Holick, M. F., Matsuoka, L. Y., and Wortsman, J. (1989). Age, vitamin D, and solar ultraviolet. Lancet 2 (8671), 1104–1105. doi:10.1016/s0140-6736(89)91124-0
Holick, M. F. (2007). Vitamin D deficiency. N. Engl. J. Med. 357 (3), 266–281. doi:10.1056/NEJMra070553
Inanir, A., Ozoran, K., Tutkak, H., and Mermerci, B. (2004). The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis. J. Int. Med. Res. 32 (6), 570–582. doi:10.1177/147323000403200602
Indhavivadhana, S., Boonyachan, W., Rattanachaiyanont, M., Wongwananuruk, T., Techatraisak, K., and Sa-Nga-Areekul, N. (2022). Effectiveness of vitamin D2 supplementation on high-sensitivity C-reactive protein and other metabolic indices in menopausal Thai women: A randomized-controlled trial. Gynecol. Endocrinol. 38 (1), 83–89. doi:10.1080/09513590.2021.1988560
Iolascon, G., Moretti, A., de Sire, A., Calafiore, D., and Gimigliano, F. (2017). Effectiveness of calcifediol in improving muscle function in post-menopausal women: A prospective cohort study. Adv. Ther. 34 (3), 744–752. doi:10.1007/s12325-017-0492-0
Iwamoto, J., Takeda, T., and Ichimura, S. (2000). Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J. Orthop. Sci. 5 (6), 546–551. doi:10.1007/s007760070003
Jackson, R. D., LaCroix, A. Z., Gass, M., Wallace, R. B., Robbins, J., Lewis, C. E., et al. (2006). Calcium plus vitamin D supplementation and the risk of fractures. N. Engl. J. Med. 354 (7), 669–683. doi:10.1056/NEJMoa055218
Jafari, T., Faghihimani, E., Feizi, A., Iraj, B., Javanmard, S. H., Esmaillzadeh, A., et al. (2016). Effects of vitamin D-fortified low fat yogurt on glycemic status, anthropometric indexes, inflammation, and bone turnover in diabetic postmenopausal women: A randomised controlled clinical trial. Clin. Nutr. 35 (1), 67–76. doi:10.1016/j.clnu.2015.02.014
Janssen, I., Katzmarzyk, P. T., and Ross, R. (2002). Body mass index, waist circumference, and health risk: Evidence in support of current national institutes of health guidelines. Arch. Intern Med. 162 (18), 2074–2079. doi:10.1001/archinte.162.18.2074
Jeon, S. W., and Kim, Y. K. (2017). Inflammation-induced depression: Its pathophysiology and therapeutic implications. J. Neuroimmunol. 313, 92–98. doi:10.1016/j.jneuroim.2017.10.016
Kamronrithisorn, T., Manonai, J., Vallibhakara, S. A., Sophonsritsuk, A., and Vallibhakara, O. (2020). Effect of vitamin D supplement on vulvovaginal atrophy of the menopause. Nutrients 12 (9), 2876. doi:10.3390/nu12092876
Karthikayan, A., Sureshkumar, S., Kadambari, D., and Vijayakumar, C. (2018). Low serum 25-hydroxy vitamin D levels are associated with aggressive breast cancer variants and poor prognostic factors in patients with breast carcinoma. Arch. Endocrinol. Metab. 62 (4), 452–459. doi:10.20945/2359-3997000000062
Kennel, K. A., Drake, M. T., and Hurley, D. L. (2010). Vitamin D deficiency in adults: When to test and how to treat. Mayo Clin. Proc. 85 (8), 752–757. doi:10.4065/mcp.2010.0138
Kerr, D. C., Zava, D. T., Piper, W. T., Saturn, S. R., Frei, B., and Gombart, A. F. (2015). Associations between vitamin D levels and depressive symptoms in healthy young adult women. Psychiatry Res. 227 (1), 46–51. doi:10.1016/j.psychres.2015.02.016
Keshavarzi, Z., Janghorban, R., Alipour, S., Tahmasebi, S., and Jokar, A. (2019). The effect of vitamin D and E vaginal suppositories on tamoxifen-induced vaginal atrophy in women with breast cancer. Support Care Cancer 27 (4), 1325–1334. doi:10.1007/s00520-019-04684-6
Lee, A., Lee, M. R., Lee, H. H., Kim, Y. S., Kim, J. M., Enkhbold, T., et al. (2017). Vitamin D proliferates vaginal epithelium through RhoA expression in postmenopausal atrophic vagina tissue. Mol. Cells 40 (9), 677–684. doi:10.14348/molcells.2017.0026
Lee, T. W., Lee, T. I., Chang, C. J., Lien, G. S., Kao, Y. H., Chao, T. F., et al. (2015). Potential of vitamin D in treating diabetic cardiomyopathy. Nutr. Res. 35 (4), 269–279. doi:10.1016/j.nutres.2015.02.005
Lerchbaum, E. (2014). Vitamin D and menopause-a narrative review. Maturitas 79 (1), 3–7. doi:10.1016/j.maturitas.2014.06.003
Li, Y. C., Kong, J., Wei, M., Chen, Z. F., Liu, S. Q., and Cao, L. P. (2002). 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 110 (2), 229–238. doi:10.1172/jci15219
Liu, C., Kuang, X., Li, K., Guo, X., Deng, Q., and Li, D. (2020). Effects of combined calcium and vitamin D supplementation on osteoporosis in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials. Food Funct. 11 (12), 10817–10827. doi:10.1039/d0fo00787k
Ma, H., Lin, H., Hu, Y., Li, X., He, W., Jin, X., et al. (2014). Serum 25-hydroxyvitamin D levels are associated with carotid atherosclerosis in normotensive and euglycemic Chinese postmenopausal women: The shanghai changfeng study. BMC Cardiovasc Disord. 14, 197. doi:10.1186/1471-2261-14-197
Martens, P. J., Gysemans, C., Verstuyf, A., and Mathieu, A. C. (2020). Vitamin D's effect on immune function. Nutrients 12 (5), 1248. doi:10.3390/nu12051248
Martins, D., Wolf, M., Pan, D., Zadshir, A., Tareen, N., Thadhani, R., et al. (2007). Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: Data from the third national health and nutrition examination survey. Arch. Intern Med. 167 (11), 1159–1165. doi:10.1001/archinte.167.11.1159
Mastaglia, S. R., Seijo, M., Muzio, D., Somoza, J., Nuñez, M., and Oliveri, B. (2011). Effect of vitamin D nutritional status on muscle function and strength in healthy women aged over sixty-five years. J. Nutr. Health Aging 15 (5), 349–354. doi:10.1007/s12603-010-0287-3
Matta Reddy, A., Iqbal, M., Chopra, H., Urmi, S., Junapudi, S., Bibi, S., et al. (2022). Pivotal role of vitamin D in mitochondrial health, cardiac function, and human reproduction. Excli J. 21, 967–990. doi:10.17179/excli2022-4935
Matyjaszek-Matuszek, B., Lenart-Lipińska, M., and Woźniakowska, E. (2015). Clinical implications of vitamin D deficiency. Prz. Menopauzalny 14 (2), 75–81. doi:10.5114/pm.2015.52149
Mei, Z., and Li, D. (2022). The role of probiotics in vaginal health. Front. Cell Infect. Microbiol. 12, 963868. doi:10.3389/fcimb.2022.963868
Mendelsohn, M. E., and Karas, R. H. (1999). The protective effects of estrogen on the cardiovascular system. N. Engl. J. Med. 340 (23), 1801–1811. doi:10.1056/nejm199906103402306
Mohanty, S., Kamolvit, W., Hertting, O., and Brauner, A. (2020). Vitamin D strengthens the bladder epithelial barrier by inducing tight junction proteins during E. coli urinary tract infection. Cell Tissue Res. 380 (3), 669–673. doi:10.1007/s00441-019-03162-z
Mosali, P., Bernard, L., Wajed, J., Mohamed, Z., Ewang, M., Moore, A., et al. (2014). Vitamin D status and parathyroid hormone concentrations influence the skeletal response to zoledronate and denosumab. Calcif. Tissue Int. 94 (5), 553–559. doi:10.1007/s00223-014-9840-0
Mosconi, L., Berti, V., Dyke, J., Schelbaum, E., Jett, S., Loughlin, L., et al. (2021). Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition. Sci. Rep. 11(1), 799. doi:10.1038/s41598-021-90084-y
Muñoz-Aguirre, P., Flores, M., Macias, N., Quezada, A. D., Denova-Gutiérrez, E., and Salmerón, J. (2015). The effect of vitamin D supplementation on serum lipids in postmenopausal women with diabetes: A randomized controlled trial. Clin. Nutr. 34(5), 799–804. doi:10.1016/j.clnu.2014.10.002
Nahas-Neto, J., Cangussu, L. M., Orsatti, C. L., Bueloni-Dias, F. N., Poloni, P. F., Schmitt, E. B., et al. (2018). Effect of isolated vitamin D supplementation on bone turnover markers in younger postmenopausal women: A randomized, double-blind, placebo-controlled trial. Osteoporos. Int. 29 (5), 1125–1133. doi:10.1007/s00198-018-4395-y
Navaneethan, P. R., Kekre, A., Jacob, K. S., and Varghese, L. (2015). Vitamin D deficiency in postmenopausal women with pelvic floor disorders. J. Midlife Health 6 (2), 66–69. doi:10.4103/0976-7800.158948
Pacini, S., Punzi, T., Gulisano, M., Boddi, V., Aterini, S., Amato, M., et al. (2008). Vitamin D receptor alleles and C-reactive protein in hemodialysis patients. Ital. J. Anat. Embryol. 113 (1), 55–62.
Peila, R., Xue, X., Cauley, J. A., Chlebowski, R., Manson, J. E., Nassir, R., et al. (2021). A randomized trial of calcium plus vitamin D supplementation and risk of ductal carcinoma in situ of the breast. JNCI Cancer Spectr. 5 (4), pkab072. doi:10.1093/jncics/pkab072
Pilz, S., Kienreich, K., Tomaschitz, A., Ritz, E., Lerchbaum, E., Obermayer-Pietsch, B., et al. (2013). Vitamin D and cancer mortality: Systematic review of prospective epidemiological studies. Anticancer Agents Med. Chem. 13 (1), 107–117. doi:10.2174/187152013804487407
Rad, P., Tadayon, M., Abbaspour, M., Latifi, S. M., Rashidi, I., and Delaviz, H. (2015). The effect of vitamin D on vaginal atrophy in postmenopausal women. Iran. J. Nurs. Midwifery Res. 20 (2), 211–215.
Rammos, G., Tseke, P., and Ziakka, S. (2008). Vitamin D, the renin-angiotensin system, and insulin resistance. Int. Urol. Nephrol. 40 (2), 419–426. doi:10.1007/s11255-007-9244-4
Rodrigues, M. H., Bruno, A. S., Nahas-Neto, J., Sandrim, V. C., Muniz, L. G., and Nahas, E. A. (2014). Evaluation of clinical and inflammatory markers of nonalcoholic fatty liver disease in postmenopausal women with metabolic syndrome. Metab. Syndr. Relat. Disord. 12 (6), 330–338. doi:10.1089/met.2013.0140
Rosen, C. J. (2011). Clinical practice. Vitamin D insufficiency. N. Engl. J. Med. 364 (3), 248–254. doi:10.1056/NEJMcp1009570
Samuel, L., and Borrell, L. N. (2013). The effect of body mass index on optimal vitamin D status in U.S. Adults: The national health and nutrition examination survey 2001-2006. Ann. Epidemiol. 23 (7), 409–414. doi:10.1016/j.annepidem.2013.05.011
Schmitt, E. B., Nahas-Neto, J., Bueloni-Dias, F., Poloni, P. F., Orsatti, C. L., and Petri Nahas, E. A. (2018). Vitamin D deficiency is associated with metabolic syndrome in postmenopausal women. Maturitas 107, 97–102. doi:10.1016/j.maturitas.2017.10.011
Schmitt, E. B., Orsatti, C. L., Cangussu, L., Bueloni-Dias, F. N., Poloni, P. F., Spadoto-Dias, D., et al. (2023). Isolated vitamin D supplementation improves the adipokine profile of postmenopausal women: A randomized clinical trial. Menopause 30 (1), 56–62. doi:10.1097/gme.0000000000002084
Schnatz, P. F., Jiang, X., Vila-Wright, S., Aragaki, A. K., Nudy, M., O'Sullivan, D. M., et al. (2014). Calcium/vitamin D supplementation, serum 25-hydroxyvitamin D concentrations, and cholesterol profiles in the Women's Health Initiative calcium/vitamin D randomized trial. Menopause 21 (8), 823–833. doi:10.1097/gme.0000000000000188
Smith, J. S., Melendy, A., Rana, R. K., and Pimenta, J. M. (2008). Age-specific prevalence of infection with human papillomavirus in females: A global review. J. Adolesc. Health 43 (4), S5–S25. doi:10.1016/j.jadohealth.2008.07.009
Sturdee, D. W., Pines, A., Archer, D. F., Baber, R. J., Barlow, D., Birkhäuser, M. H., et al. (2011). Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 14 (3), 302–320. doi:10.3109/13697137.2011.570590
Sutton, A. L., and MacDonald, P. N. (2003). Vitamin D: More than a "bone-a-fide" hormone. Mol. Endocrinol. 17 (5), 777–791. doi:10.1210/me.2002-0363
Usategui-Martín, R., Pérez-Alonso, M., Socorro-Briongos, L., Ruiz-Mambrilla, M., De Luis, D., Linares, L., et al. (2019). Estrogen receptor genes polymorphisms determine serum lipid profile in healthy postmenopausal women treated with calcium, vitamin D, and genistein. J. Cell Biochem. 120 (8), 13115–13120. doi:10.1002/jcb.28584
Vacek, J. L., Vanga, S. R., Good, M., Lai, S. M., Lakkireddy, D., and Howard, P. A. (2012). Vitamin D deficiency and supplementation and relation to cardiovascular health. Am. J. Cardiol. 109 (3), 359–363. doi:10.1016/j.amjcard.2011.09.020
Vanoirbeek, E., Krishnan, A., Eelen, G., Verlinden, L., Bouillon, R., Feldman, D., et al. (2011). The anti-cancer and anti-inflammatory actions of 1,25(OH)₂D₃. Best. Pract. Res. Clin. Endocrinol. Metab. 25 (4), 593–604. doi:10.1016/j.beem.2011.05.001
Wang, D., Vélez de-la-Paz, O. I., Zhai, J. X., and Liu, D. W. (2013). Serum 25-hydroxyvitamin D and breast cancer risk: A meta-analysis of prospective studies. Tumour Biol. 34 (6), 3509–3517. doi:10.1007/s13277-013-0929-2
Zhang, W. Y., Guo, Y. J., Wang, K. Y., Chen, L. M., and Jiang, P. (2020). Neuroprotective effects of vitamin D and 17ß-estradiol against ovariectomy-induced neuroinflammation and depressive-like state: Role of the AMPK/NF-κB pathway. Int. Immunopharmacol. 86, 106734. doi:10.1016/j.intimp.2020.106734
Keywords: vitamin D, menopause, osteoporosis, cardiovascular disease, genitourinary syndrome of menopause
Citation: Mei Z, Hu H, Zou Y and Li D (2023) The role of vitamin D in menopausal women’s health. Front. Physiol. 14:1211896. doi: 10.3389/fphys.2023.1211896
Received: 26 April 2023; Accepted: 05 June 2023;
Published: 12 June 2023.
Edited by:
Alex Rafacho, Federal University of Santa Catarina, BrazilReviewed by:
Melissa Melough, University of Delaware, United StatesOlha Lisakovska, Palladin Institute of Biochemistry (NAS Ukraine), Ukraine
Copyright © 2023 Mei, Hu, Zou and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dandan Li, li226dan@163.com