Sarebani et al. BMC Women's Health (2020) 20:27 https://doi.org/10.1186/s12905-020-00899-6 STUDY PROTOCOL Open Access Investigating the effect of vitamin D vaginal suppository on sexual function among postmenopausal women: study protocol for a randomized controlled trial Zinat Sarebani1, Zainab Alimoradi2* , Ehsan Aali3, Monirsadat Mirzadeh4, Venus Chegini5, Mohammadreza Abbaspour6 and Mark D. Griffiths7 Abstract Background: Menopause is associated with changes in sexual function which are partly due to vaginal atrophy in response to estrogen reduction. Estrogen administration temporarily reduces the symptoms of vaginal dryness, but long-term exposure to this drug is likely to be associated with serious complications. Considering the promising results of previous studies concerning the effect of vitamin D on vaginal dryness, the proposed study will investigate the effect of vitamin D vaginal suppository on the sexual function of postmenopausal women. Methods: In a randomized, controlled clinical trial, 105 postmenopausal women will be randomly assigned to three groups receiving vitamin D vaginal suppository, placebo vaginal suppository, or control (no intervention). Vitamin D vaginal suppositories contain 1000 units of vitamin D3. The timing of the use of vitamin D vaginal suppositories and placebo suppositories will be every night in the first 2 weeks, and every other night in the following 6 weeks (8 weeks in total). The primary outcome will be the sexual function of participants which will be assessed using the Female Sexual Function Index (FSFI) before and immediately after the intervention, and at 1 and 2 months after the end of the intervention. The side effects of these suppositories will be examined as a secondary consequence of the study. Data will be analyzed using SPSS software version 25. In the case of normal distribution of data, the mean score of sexual function will be compared between the groups using a repeated measurements ANOVA. If statistical analysis leads to significant results, the post-hoc test will be used to determine the differences between the groups. Comparison of demographic and fertility characteristics of the women will be carried out using statistical tests such as chi-squares and t-tests. A significance level of p < .05 will be used for statistical analyses. Discussion: If vitamin D vaginal suppositories improve sexual function among premenopausal women with long- term effects and minimum side effects, the suppositories will be considered a safe complementary and alternative choice for alleviating sexual dysfunction among this group. Trial registration: IRCT20180704040346N1 at 2018-10-13 prospectively registered. Keywords: Menopause, Sexual function, Vitamin D vaginal suppository * Correspondence: [email protected]; [email protected] 2Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Bahonar blv., Qazvin 34197-59811, Iran Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sarebani et al. BMC Women's Health (2020) 20:27 Page 2 of 8 Background estrogen deficiency is the main cause of vaginal atrophy, Menopause – as one of the critical and inevitable stages estrogen therapy after menopause is the most rational of women’s life – is the most important event during choice of treatment. Systemic estrogen therapy is the middle age. It can have a particular influence in women’s gold standard in slowing down and/or preventing early personal, cultural, social, reproductive health, and sexu- genital atrophy, but maintaining its effect requires con- ality [1]. Menopause leads to many physiological changes tinuous treatment [2]. The other initial and preferable that occur continuously and gradually, and can affect the and choice in treating genitourinary syndrome of meno- woman’s life [2]. Menopause occurs gradually from the pausal women is ultralow-dose topical estriol [16]. Over- late third decade of life between the ages of 40 and 60 all, due to the potential risks of postmenopausal years and a mean of 51 years [1]. According to studies systemic hormone replacement therapy, estrogen re- conducted in Iran, the range of menopausal age ranges placement therapy may not be acceptable by many between 46 and 52 years [3]. women [8]. Concerns about the complications of estro- The climacteric phase and menopause are the periods gen therapy, including cardiovascular events, thrombo- of reductions in the production of hormones, that can embolism, breast cancer, and endometrial hyperplasia affect women’s quality of life because of various compli- are the most important reasons for the low acceptance cations [4]. These complications can include symptoms of synthetic estrogen therapy [17]. In addition to the such as hot flushes, night sweats, palpitations, bone loss, aforementioned concerns, a considerable proportion of urinary problems, and vaginal dryness [5]. Vaginal dry- menopausal women experience some type of chronic ness (as one of the problems caused by the reduction of disease such as diabetes, cardiovascular disease, dyslipid- estrogen production) is due to thinning of the endomet- emia, and asthma [18], so they are not good candidates rial tissue and increase of pH, that cause local itching, when administering many kinds of hormone therapy. an increase in the incidence of vaginal infection, and va- Regarding these issues, there is an increasing tendency ginal structural weakness. In addition, dyspareunia can to utilize alternative treatments for relieving menopausal cause sexual dysfunction and loss of sexual desire during symptoms [17]. menopause [6]. Vaginal atrophy, after hot flushes, is the Vitamin D is one of the essential substances in meta- second most common complication and is the worst bolic and physiological processes in the body [19]. Recent complication of menopause [4]. Reducing estrogen levels literature has reported the role of low level of vitamin D in through causing fractures in collagen and elastin fibers many pathological conditions including cardiovascular in the vagina causes vaginal atrophy. From a cytomor- disease, type 2 diabetes mellitus, metabolic syndrome, can- phological aspect, parabasal cells are increased and inter- cer, and increased mortality, as well as its role in calcium mediate and superficial cells are decreased [7]. and bone metabolism [20]. Recent research has also Problems with vaginal atrophy are clinically manifested shown that vitamin D3 may be useful in preventing vagi- 4–5 years after the beginning of menopause [8]. Vulvovagi- nal atrophy. Vitamin D3 may play a role in regulating the nal atrophy lead to vaginal dryness, irritation, soreness, and growth and differentiation of the vaginal epithelium. Cost- consequently dyspareunia [9, 10]. Approximately one-third antino’s research found that taking vitamin D3 can help of postmenopausal women report painful intercourse (dys- prevent osteoporosis and eliminate vaginal discomfort pareunia), lack of moisture, and decreased lubrication [11]. after the menopause [6]. Vitale et al. (2018) reported after Common symptoms of atrophy include vaginal dryness, a randomized, placebo-controlled trial, that oral supple- burning, post-coital bleeding, and pain [12]. In clinical ments of vitamin D in combination with isoflavones, cal- examination, symptoms such as being pale, the reduction cium, and inulin significantly improved the sexual of transverse vaginal folds (roga), petechiae, reduced elasti- function of menopausal women [21]. In a cross-sectional city, and dryness confirms the presence of atrophy [5]. Va- study, Yildirmal et al. (2004) showed that the use of vita- ginal atrophy is one of the causes of sexual problems, and is min D supplements was effective in the maturation of va- one of the most important complaints among women dur- ginal cells [22]. Also, a clinical trial by Zainlugl et al. ing the menopause, but despite many advances in the pre- (2007) showed that in postmenopausal women with osteo- vention and treatment of menopausal complications, sexual porosis, Raloxifene and vitamin D supplementation signifi- problems are underestimated [13]. cantly reduced vaginal dryness and pH [23]. One of the therapeutic methods for improving the Vitamin D3 can be absorbed in the vagina by applying symptoms of vaginal atrophy and dyspareunia in post- a vaginal suppository [11]. The results of a clinical trial menopausal women is estrogen therapy [14]. Estrogen study by Rad et al. (2014) on postmenopausal women in improves the mucosa, and increases elasticity and blood Ahwaz (Iran) showed that vitamin D suppositories could flow to vulva and vaginal area. It also increases the sen- experimentally (according to the results of the partici- sory threshold of the vulva region and vagina, increases pants’ Pap smear) improve dryness and cell proliferation sexual pleasure, and improves