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Revista Peruana de Ginecología y Obstetricia
versión On-line ISSN 2304-5132
Rev. peru. ginecol. obstet. vol.68 no.1 Lima ene./mar. 2022 Epub 24-Feb-2022
http://dx.doi.org/10.31403/rpgo.v68i2387
Special Articles
Vitamin D deficiency and gynecological pathologies in women of reproductive age
1. School of Medicine, The University of Zulia, Maracaibo, Zulia State, Venezuela
2. Obstetrics and Gynecology Department, Hospital Central "Dr. Urquinaona", Maracaibo, Zulia State, Venezuela
Vitamin D is currently under investigation in many fields of medicine. It is known to have fundamental functions in calcium metabolism and bone modeling. Vitamin D deficiency defined as 25-hydroxychalciferol concentration < 20 ng/mL and is frequently observed in patients with gynecological pathologies. In the last two decades there is evidence on the association of low serum vitamin D concentrations with disorders such as diabetes mellitus and metabolic syndrome. There are increasing reports of the impact of vitamin D metabolism on the development of disorders of the female reproductive system. Vitamin D receptor and 1α-hydroxylase are present in the reproductive organs, suggesting that vitamin D may have some effect in modulating cellular functions. The detrimental effects of deficiency have been shown in patients diagnosed with polycystic ovarian syndrome, endometriosis, and leiomyomatosis. Vitamin D supplementation should be added to the treatment schemes of most gynecologic pathologies in patients with deficiency, both for the improvement of insulin resistance (as in patients with polycystic ovarian syndrome) and for the outcomes of infertility treatment. The aim of this review was to establish effects of vitamin D deficiency on pathologies in women of reproductive age.
Key words: Vitamin D; Polycystic ovary syndrome; Uterine leiomyomatosis; Endometriosis; In vitro fertilization
Introduction
Epidemiological studies suggest that global vitamin D (VitD) deficiency is about 90%. Despite indications for supplementation, deficiency is still important and includes women of childbearing age. Deficiency is defined as 25-hydroxyvitamin [25(OH)D; main circulating form] concentrations below 20 ng/mL; suboptimal values correspond to 20 and 30 ng/mL, whereas serum concentrations of 30 to 50 ng/mL are considered optimal to ensure pleiotropic effects1. There are few data on VitD concentrations in the Latin American population. However, studies in different adult populations have shown a high prevalence of moderate deficiency in the world population2.
In the last three decades, several investigations have evaluated the therapeutic effects of VitD other than bone metabolism. It has beneficial effects on autoimmune, infectious, cardiovascular, insulin resistance and malignant neoplasms3. However, studies evaluating the effects on gynecological pathologies are scarce4. Since both VitD receptors and 1α-hydroxylase are present in reproductive tissues (ovaries, uterus and pituitary), the potential association between VitD deficiency and gynecological pathologies is evident5. The objective of this review was to establish the effects of vitamin D deficiency on pathologies in women of reproductive age.
Vitamin D metabolism
VitD is an essential fat-soluble vitamin and its pleiotropic effects are closely related to health and disease1. Its biological cycle begins when 7-dehydrocholesterol is transformed by the effects of ultraviolet B radiation (wavelength 290 to 315 nm) in epidermal keratinocytes and dermal fibroblasts into previtamin D. Less than 10% comes from food sources or dietary supplements. In the liver and kidneys it is converted into two main metabolically active forms: cholecalciferol (VitD3) and ergocalciferol (VitD2). This process is extremely efficient, since a brief daily exposure to sunlight of the surface of the hands and face is equivalent to the intake of 200 units of VitD6.
It is difficult to determine the duration of daily exposure to sunlight necessary to achieve the amount provided by supplements in individual patients and depends on skin type, latitude, season and time of day7. Prolonged exposure to sunlight does not produce toxic concentrations of VitD, mainly due to photoconversion to inactive metabolites (lumisterol, tachysterol, 5,6-transVitD and suprasterols). In addition, sunlight induces melanin production, which contributes to decrease its production8.
Vitamin D in gynecological pathologies and reproductive medicine
Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age with heterogeneous clinical manifestations. In addition to menstrual alterations, ovaries with polycystic changes, hyperandrogenism and/or hyperandrogenemia, a group of patients present obesity - overweight (20% and 85%), insulin resistance and cardiovascular and metabolic disorders9-11.
A meta-analysis showed that a 1 kg/m2 increase in body mass index (BMI) correlated with a greater than 1% decrease in VitD concentrations. Similarly, a 10% increase in BMI was associated with a greater than 4% decrease in serum concentrations. These observations confirm that overweight-obesity, present in most PCOS patients, leads to VitD deficiency. The main pathophysiological mechanism proposed is sequestration by adipose tissue9.
There is no clear evidence indicating the possible association between low VitD concentrations and the pathogenesis of PCOS, especially in patients with normal weight10,11. There is evidence of correlations between VitD concentrations and androgen, luteinizing hormone and follicle stimulating hormone values12. However, other investigations have not confirmed these findings13,14. Other studies have found an association between low serum VitD concentrations and insulin resistance, impaired glucose tolerance, dyslipidemia, obesity and hypertension in these patients13-15.
VitD may have beneficial metabolic effects by stimulating insulin receptor expression, leading to improved glycemic metabolism. Activation of the insulin promoter gene produces changes in extra- and intracellular calcium stores that modulate insulin secretion. The Apa-I polymorphism of the VitD receptor gene may contribute to the development of PCOS16. Other polymorphisms (Cdx-2, Taq-I, Bsm-I) appear to be associated with alterations in glycemic metabolism, hyperandrogenemia, increased concentrations of luteinizing hormone and follicle stimulating hormone with decreased sex hormone binding globulin17,18.
The therapeutic efficacy of VitD supplementation in PCOS patients has been evaluated by several studies. VitD and calcium supplementation produced normalization of menstrual cycles after initiation of treatment19. Another study showed regularization of menstrual cycles in half of the cases, as well as improvement of insulin resistance, without significant changes in BMI15. Two other studies showed that supplementation improved insulin sensitivity and lipid profile, without other significant metabolic effects20,21. An investigation of VitD and calcium supplementation found significant decreases in testosterone and androstenedione concentrations, accompanied by a decrease in blood pressure, with no effect on fasting glycemia and insulin concentrations22. Other studies have provided evidence that supplementation can repair folliculogenesis alterations and induce spontaneous ovulations23.
There is still controversy about the effects of VitD supplementation on metabolic disorders in PCOS patients. One investigation showed improvement of lipid profile with no effect on inflammatory markers24. Meanwhile, VitD supplementation alone or combined with metformin did not produce changes in insulin resistance despite normalization of blood pressure values25. Finally, other research has shown beneficial effects of VitD supplementation on ovulation stimulation with clomiphene citrate and increased success rate of in vitro fertilization (IVF) procedures in infertile PCOS patients26.
Endometriosis
The presence of VitD receptors and metabolic enzymes in human endometrium and myometrium has been confirmed. Due to the immunomodulatory, antiproliferative and anti-inflammatory properties of VitD, there is growing interest in the possible etiopathogenesis of endometriosis27,28.
A case-control study showed that serum VitD concentrations were elevated in patients with endometriosis27. Subsequent studies showed overexpression of VitD receptors and 1α-hydroxylase in peritoneal foci and endometrium of patients with endometriosis compared with healthy controls. This could indicate that there is immune hypersensitivity at normal concentrations in patients with endometriosis and immune overstimulation at elevated peritoneal VitD concentrations. These effects would be auto- and/or paracrine within the implants28. Another investigation of serum from endometriosis patients found increased expression of VitD-binding protein29. Similar results have also been obtained in ectopic endometrial tissue30.
Some authors suggest that the elevated serum VitD concentrations and receptor overexpression in endometriotic foci may be the result of inadequate selection of the control groups, which included patients with uterine myomas and idiopathic infertility, conditions characterized by VitD deficiency31. In addition, these studies have small sample groups, great heterogeneity and retrospective design.
Investigations of the association between VitD intake and serum concentrations in patients with endometriosis confirmed that serum concentrations correlated negatively with the presence of endometriosis foci. In addition, patients with the highest VitD concentrations had a 24% lower risk of developing endometriosis compared to the group of patients with lower concentrations. On the other hand, women with higher dietary intake had 21% lower risk than those patients with lower concentrations32. These findings were confirmed by research with elocalcitol (a selective VitD receptor agonist) by inhibiting the development of endometriotic foci and reducing inflammatory markers33,34.
Infertility and assisted reproduction
Several in vitro and in vivo studies document the association between VitD deficiency and ovarian dysfunction. VitD regulates the expression of receptors for follicle-stimulating and antimüllerian hormone, controlling both folliculogenesis and granulosa cell differentiation. It also increases the expression of steroidogenic enzymes and stimulates progesterone-estrogen production, controlling corpus luteum development35.
Mice lacking the VitD receptor gene have impaired folliculogenesis, anovulation and uterine hypoplasia. In addition, VitD-deficient diet causes decreased fertility36. Clinical studies of the association between VitD deficiency and infertility, response to ovulation stimulation and efficacy of IVF methods are scarce and offer contradictory data. Some publications indicate high rates of deficiency (between 20% and 100%) in patients undergoing IVF programs37-39. A prospective investigation showed a positive correlation between VitD concentrations and the percentage of pregnancies achieved in an IVF program10. Higher nidation rates were achieved in women whose follicular fluid VitD concentrations were higher37.
One study found that serum VitD concentrations affect the efficacy of IVF procedures. Linear decreases in concentrations were associated with decreased pregnancy rates. But concentrations did not affect ovulation stimulation or resulting embryos38. Other research showed that higher VitD concentrations were associated with higher pregnancy rates and live births (37% vs. 78%)39. Other research that evaluated single blastocyst transfer on day 5 found lower pregnancy rates in VitD-deficient women (41% compared with 54%). The probability of achieving a pregnancy in the deficiency group was 40% lower compared to the control group40. In contrast, the absence of association between the efficacy of blastocyst transfer on day 5 with VitD deficiency was shown by a later study41.
Although most data indicate an association between VitD deficiency and IVF failure, other studies have not confirmed this relationship. One group showed adverse effects of high VitD concentrations on embryo quality42. No effects on IVF efficacy have been observed either, regardless of the determination of total or available VitD43.
These contradictory findings are probably due to confounding factors, different definitions of deficiency and methodologies of VitD determination and transfer of different numbers of embryos. Nevertheless, most of the available studies suggest a possible causal relationship. Given the prevalence of VitD deficiency in infertile women and low cost of supplementation, the current recommendation is the routine determination of concentrations and the use of supplementation before initiating any IVF program31.
Uterine leiomyomas
Several investigations have shown that VitD deficiency may be a risk factor for the development of uterine leiomyomas, regardless of ethnicity44. One study found that serum concentrations were significantly lower in patients with leiomyomas. After adjustment for BMI, ancestry, and ethnicity, this association remained significant45.
The antiproliferative effects of VitD on human myometrial and leiomyoma-derived cells have been documented in in vitro studies46,47. It inhibits both Wnt4/β-catenin and signal transduction of the target pathway of rapamycin in mammalian cells, key pathways in the etiopathogenesis of leiomyomas. The potential therapeutic effect during the formation and/or growth of leiomyomas has also been documented in in vivo animal models48.
Conclusion
VitD deficiency is a public health problem. Available evidence indicates that it is related to potential health complications in women of reproductive age. Deficiency appears to be related to endocrine and gynecological diseases. Differences in study methodologies, geographic location, season of the year and exposure to sunlight may explain the discrepancies between different population groups. Patients with proven deficiency may benefit from supplementation.
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Statement of responsibility of the authors
Ethical responsibilities: Protection of persons. The authors declare that the procedures followed conformed to the ethical standards of the committee on responsible human experimentation and in accordance with the World Medical Association and the Helsinki Declaration of 1975 in its most current version.
Funding: The authors certify that we have not received financial support, equipment, personnel or in-kind support from individuals, public and/or private institutions for the realization of the study.
Article publication rights: The authors declare that the publication rights of the manuscript will be assigned exclusively to the journal in case of publication. And we also authorize the electronic dissemination of the same.
Received: October 25, 2021; Accepted: December 01, 2021; pub: February 22, 2022
Este es un artículo publicado en acceso abierto bajo una licencia Creative Commons
