Skip to main content
Download PDF

The efficacy of oxytocin gel in postmenopausal women with vaginal atrophy: an updated systematic review and meta-analysis

BMC Women's Health volume 23, Article number: 494 (2023) Cite this article

Abstract

Background

Genitourinary syndrome of menopause (GSM) is a common and disturbing issue in the postmenopausal period. Unlike vasomotor symptoms, it has a progressive trend. Our study aims to evaluate the efficacy and safety of oxytocin gel versus placebo gel in postmenopausal women with GSM.

Methods

A systematic review and meta-analysis synthesizing randomized controlled trials (RCTs) from Web of Science, SCOPUS, PubMed, and Cochrane Central Register of Controlled Trials databases on January 18, 2023. Keywords such as “oxytocin,“ “intravaginal,“ “vaginal,“ “atrophic,“ and “atrophy” were used. We used Review Manager (RevMan) version 5.4 in our analysis. We used the risk ratio (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes; both were presented with the corresponding 95% confidence interval (CI) and were calculated with the Mantel-Haenszel or inverse variance statistical method. Cochrane’s Q test and the I2 statistic were used as measures of statistical inconsistency and heterogeneity. The Cochrane Risk of Bias Tool for RCTs was used for the quality assessment of the included studies.

Results

Seven studies with 631 patients were included. Regarding the maturation index, there was a statistically insignificant increase in the oxytocin arm (MD = 12.34, 95% CI (-12.52-37.19), P = 0.33). Clinically assessed vaginal atrophy showed a statistically significant reduction in the oxytocin group (RR = 0.32, 95% CI (0.23 − 0.10), P < 0.00001). For dyspareunia, vaginal pH, and histological evaluation of vaginal atrophy, there was a statistically insignificant difference between the two groups (RR = 1.02, 95% CI (0.82–1.27), P = 0.84), (MD = -0.74, 95% CI (-1.58-0.10), P = 0.08), and (MD = -0.38, 95% CI (-0.82-0.06), P = 0.09), respectively. There was no significant difference in the safety profile between the two groups as measured by endometrial thickness (MD = 0.00, 95% CI (-0.23-0.23), P = 0.99).

Conclusions

Although oxytocin has been proposed as a viable alternative to estrogen in the treatment of GSM, our findings show the opposite. Larger, high-quality RCTs are needed to confirm or refute our results.

Trial registration

PROSPERO registration number CRD42022334357.

Peer Review reports

Background

Menopause is defined as the spontaneous stoppage of menses for 12 months [1]. After menopause, estrogen levels decrease markedly due to the loss of the ovarian ability to produce it. Estrogen deficiency is accompanied by broad systemic, histological, and cytological changes. These changes can cause various signs and symptoms like vasomotor hot flushes, sleep disturbances, mood changes, loss of skin elasticity, and Genitourinary syndrome of menopause (GSM), reducing the quality of life (QOL) in the affected postmenopausal women [2, 3]. The genitourinary syndrome of menopause is a fairly new concept describing the decadence of the vaginal and urethral tissue, causing various signs and symptoms, including not only dryness and itching in the genital area but also painful sexual life and lower urinary tract symptoms like urgency, dysuria, and recurrent urinary tract infections [4, 5]. The introduction of the new name was to overcome the restrictive vision of the previously used terms, such as vulvovaginal atrophy and atrophic vaginitis, which did not cover the whole scope of the subject, discarding the urinary symptoms and not linking these symptoms to estrogen decline after menopause [5].

GSM is a common health issue affecting up to 70% of postmenopausal women [6]. Within 6 years of menopause, 84% of menopausal women reported GSM [7]. In addition, 75% of women with GSM felt that GSM had a negative impact on their lives [8]. Furthermore, GSM symptom severity was associated with a worse quality of life [9], and unlike vasomotor symptoms, GSM is a progressive disease that rarely improves without treatment.

Vaginally administered estrogen is the most studied intervention and the mainline of treatment to antagonize urogenital aging and improve the QOL in this population of patients [10]. Nonetheless, the safety profile of estrogen is controversial in the long run due to the fear of increasing the risk of certain types of cancer and thromboembolic events; we need to mention that this quarrel is due to limited data [11]. New, non-estrogenic treatment options are imperative to provide an alternative to estrogen, especially when there is a concern about developing estrogen-related cancers. Oxytocin is a new modality to counteract vaginal atrophy studied in preclinical and clinical trials [12,13,14,15,16,17,18,19].

Oxytocin is a pituitary hormone formed of nine amino acids in the hypothalamus’s supraoptic and paraventricular neurons, stored in the posterior pituitary gland, and released directly into the blood via exocytosis [20]. The major role of oxytocin was confined to the obstetric field in inducing labor and reducing postpartum hemorrhage. However, research has shed light on other facets of oxytocin and widened the scope of its clinical applications [21].

Intravaginally applied oxytocin preparations work directly on its receptors in the lower genitourinary tract, thus avoiding or at least reducing its unwanted systemic actions [22]. Oxytocin can stimulate mitotic divisions by enhancing the production of multiple growth factors, mucosal blood flow, and wound healing, thus antagonizing urogenital aging [12].

There is a previously published meta-analysis on the same topic [13], but its main defect was its limited sample size of 388 participants. It also missed reporting important outcomes such as vaginal pH, clinically assessed vaginal atrophy, and dyspareunia. Furthermore, it did not address the high heterogeneity between the studies. Our objective is to update the previous study [13] with a further one included study increasing the sample size to 545 participants, representing about 40% of its sample size. We also addressed the missing outcomes and the high heterogeneity. Therefore, we have conducted a more comprehensive and updated meta-analysis to assess the efficacy and safety of intravaginal oxytocin gel in postmenopausal women with vaginal atrophy.

Methods

The PRISMA guidelines for reporting systematic reviews and meta-analyses of randomized controlled trials (RCTs) were used as guidance by the authors [23]. This systematic review was registered within the International Prospective Register of Systematic Reviews (PROSPERO), registration identifier CRD42022334357.

Eligibility criteria

Only randomized control trials comparing oxytocin preparations with a placebo for relieving vaginal atrophy were included in this study. We included RCTs only as they are the highest level of evidence to establish causal associations. There were no restrictions concerning race, country, or time of publication. We included the studies based on the PICO criteria: patients, intervention, control, and outcomes. The participants of interest were postmenopausal women, who were defined as women aged more than 40 years with spontaneous or surgical menopause, who had their last menstruation 12 months before the study, or who had a serum follicle-stimulating hormone (FSH) level ≥ 40 IU/L. We used a broad definition of postmenopause to increase our sample size. The intervention was intravaginal oxytocin forms (such as Pitocin, Syntocinon, and Vagitocin). The comparator was placebo. To be included, studies must have measured and reported our outcomes of interest. No limits concerning the time of follow-up were used.

Our exclusion criteria were: non-randomized studies, animal studies, conference abstracts, non-English papers, and single-arm studies. We excluded studies that compared oxytocin to active control, as our objective was to establish if intravaginal oxytocin has any beneficial effect in women with GSM and not to compare its efficacy to other active treatments. Outcomes and study results that had different measurement units or were reported in a way that could not be pooled together in a meta-analysis were excluded.

Information sources

Relevant articles were identified through a comprehensive search on PubMed, Web of Science, Cochrane, and Scopus databases from inception to January 18, 2023. The reference lists of the eligible papers were also searched to find other relevant studies.

Search strategy

A search was carried out for randomized controlled trial studies published in PubMed, Web of Science, Scopus, and Cochrane with no language and time restrictions using the following query: (Oxytocin OR Pitocin OR Syntocinon OR Vagitocin OR Duratocin OR Carbetocin) AND ((Intravaginal OR vaginal OR Vulvovaginal OR dyspareunia OR urogenital OR uro-genital OR Vulvar OR vulvo‐vaginal) AND (atrophic OR atrophy OR vaginitides OR vaginitis OR atrophies OR lubrication OR dryness)). The full search strategy for each database is shown in Additional file 1.

Selection process

Using Endnote, all records were pooled. The data were exported to an Excel sheet, and then this Excel sheet was submitted through two phases to find eligible studies. First is the title and abstract screening phase, and articles that pass this phase move on to the full-text screening phase. Worth noting is that each article’s eligibility in each phase was evaluated by two authors independently, then discussed. Any conflicts were resolved by a third senior author.

Data collection process

The lead author prepared formatted Excel sheets including baseline data and study characteristics, as well as ROB assessment and outcomes of interest. Data from each study were extracted by two authors independently, then discussed. Any conflicts were resolved by a third senior author. Any incomplete or incompatible data have been dealt with using methods recommended in the Cochrane Handbook [24].

Data items (outcomes)

The primary outcome was the cytological assessment of vaginal atrophy (Vaginal Maturation Index), which is the relative proportion of superficial cells, intermediate cells, and parabasal cells. Maturation index = Superficial cells (%) + 0.5 × Intermediate cells (%). Secondary outcomes included laboratory indicators of vaginal atrophy, such as vaginal pH and histological assessment of vaginal atrophy; clinically objective indicator of vaginal atrophy assessed by the physical examination of the vulva and vagina or by colposcopic examination, dyspareunia, which is a subjective indicator of vaginal atrophy; and the safety profile measured by the endometrial thickness.

Data items (other variables)

Two review authors extracted the characteristics of the studies and baseline data. Study characteristics included study ID, name and dose of the intervention and control, sample size, study design, follow-up duration, inclusion and exclusion criteria, and the results. Baseline data included the age, body mass index, and years after menopause.

Study risk of bias assessment

The quality of the included studies was assessed with the Cochrane Risk of Bias Tool for RCTs [25]. The quality of each study was evaluated by two authors independently, then discussed. Any conflicts were resolved by a third senior author. A funnel plot was used to assess publication bias.

The tool consists of the following domains: random sequence generation (selection bias), allocation sequence concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessors (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other bias. Author judgments fall into three categories: low, unclear, or high risk of bias for each domain.

According to Egger’s funnel-plot-based methods, we could not assess the risk of publication bias due to the small number of included studies [26].

Effect measures and statistical synthesis

The statistical analyses were used according to the guidelines in the Cochrane Handbook for the systematic review of interventions [24]. We used Review Manager (RevMan) version 5.4 [27]. All data were collected as means ± standard deviation (SD), or event and total for continuous and dichotomous outcomes, respectively. The continuous outcome data of maturation index, vaginal pH, histological evaluation of vaginal atrophy, and endometrial thickness were measured using the inverse variance statistic method and reported as mean differences with a 95% confidence interval (CI), and we used the Mantel-Haensze equation to calculate the pooled RR and 95% CI for dichotomous variables, such as clinically assessed vaginal atrophy and dyspareunia. A P value of < 0.05 was considered statistically significant. We used Cochrane’s Q test and the I2 statistic as measures of statistical inconsistency and heterogeneity. A random-effects model was used if there was significant heterogeneity as determined by a P value less than 0.05 or I2 higher than 60%; otherwise, we used a fixed-effects model. We used the leave-one-out method to solve and detect the cause of heterogeneity.

Results

Search results

Our search, carried out on January 18, 2023, retrieved 3,947 articles: 2,345 from PubMed, 1,509 from Cochrane, 70 from Scopus, and 23 from Web of Science. After the removal of duplicates, the total number was 3123. Following title and abstract screening, only 35 papers were eligible for full-text screening. Finally, seven papers were found to be eligible for the final analysis. The PRISMA flow diagram is shown in Fig. 1.

Fig. 1
figure 1

 A flowchart shows the detailed process of the search strategy and study selection

Full size image

Study characteristics

The seven included studies [14,15,16,17,18,19, 28] were double-blinded, randomized, placebo-controlled trials published between 2011 and 2020, with different follow-up periods ranging from 7 to 14 weeks in AL-saqi et al. studies [18, 19], one month in Torky et al. [15], eight weeks in Abedi et al. [17] and Zohrabi et al. [28], and 1,12 weeks in Jonasson et al. studies [14, 16]. Four trials were conducted in Sweden [14, 16, 18, 19], two in Iran [17, 28], and another one in Egypt [15]. All included studies used intravaginal oxytocin gel versus placebo, with different oxytocin doses ranging from 100 to 400 and 600 IU. Table 1 presents the study summary of the included studies.

Table 1 Summary of included studies
Full size table

These seven eligible papers examined 545 healthy postmenopausal women over the age of 40. There were other inclusion criteria for women to be included in the studies, which were assessed through gynecological examination and cytological evaluations, such as that their last menstruation must be more than one year prior to the study, vaginal pH > 5, body mass index (BMI) < 29 kg/m2, plasma follicle stimulating hormone (FSH) levels > 40 IU/L, 17b-estradiol levels < 70 pmol/L, superficial cells < 5%, endometrial thickness < 4 mm, and a score of sexual function < 26 according to the Female Sexual Function Index (FSFI). Table 2 presents baseline characteristics for the population of the included studies.

Table 2 Baseline characteristics for population of the included studies
Full size table

Quality of included studies

The quality of the included studies was evaluated with the Cochrane Risk of Bias Tool for Randomized Control Trials. The assessment of several sources of bias revealed that all studies had an adequate generation of allocation concealment and appeared to be free from performance, detection, and attrition bias. Three studies [17, 19, 28] were at unclear risk of selection bias related to random sequence generation. The study by Jonasson et al. [14] was at unclear risk of reporting bias. The summary of quality assessment domains is shown in Fig. 2.

Fig. 2
figure 2

Summary of assessment of the risk of bias

Full size image

Primary outcome

Maturation index

Regarding the maturation index, three trials [18, 19, 28] with a total of 120 patients in the oxytocin arm and 107 patients in the placebo arm were included in the analysis. There was a statistically insignificant increase in the oxytocin arm over the placebo arm (MD = 12.34, 95% CI (-12.52-37.19), P = 0.33) (Fig. 3a). The random effect model was used due to significant heterogeneity (I2 = 97%, P < 0.00001), which became homogenous (I2 = 0%, P = 0.97) after omitting Zohrabi et al. [28] without significant change in the pooled analysis (MD = 3.02, 95% CI (-4.08-10.12), P = 0.4) (Fig. 3b).

Fig. 3
figure 3

 A forest plot shows the mean difference of change in the maturation index (a). (b) shows the results after excluding Zohrabi et al.

Full size image

Secondary outcomes

Vaginal pH

Regarding vaginal pH, three trials [16, 18, 28] with a total of 155 patients in the oxytocin arm and 148 patients in the placebo arm were included in the analysis. There was a statistically insignificant decrease in the oxytocin arm over the placebo arm (MD = -0.50, 95% CI (-1.69-0.69), P = 0.41) (Fig. 4a). The random effect model was used due to significant heterogeneity (I2 = 95%, P < 0.00001), which became homogenous (I2 = 5%, P = 0.35) after omitting Zohrabi et al. [28] without significant change in the pooled analysis (MD = 0.17, 95% CI (-0.16-0.50), P = 0.31) (Fig. 4b).

Fig. 4
figure 4

 A forest plot shows the mean difference of change in vaginal pH (a). (b) shows the results after excluding Zohrabi et al.

Full size image

Clinically assessed vaginal atrophy

Regarding clinically assessed vaginal atrophy, two trials [14, 15] with a total of 80 patients in the oxytocin arm and 80 patients in the placebo arm were included in the analysis. There was a statistically significant decrease in the oxytocin arm over the placebo arm (RR = 0.32, 95% CI (0.23 − 0.10), P < 0.00001). The pooled studies were homogenous (I2 = 0%, P = 0.93) (Fig. 5).

Fig. 5
figure 5

 A forest plot shows the risk ratio of patients with vaginal atrophy

Full size image

Dyspareunia

Regarding dyspareunia, two trials [15, 28] with a total of 115 patients in the oxytocin arm and 185 patients in the placebo arm were included in the analysis. There was a statistically insignificant risk in the oxytocin arm over the placebo arm (RR = 1.02, 95% CI (0.82–1.27), P = 0.84). The pooled studies were homogenous (I2 = 0%, P = 0.78) (Fig. 6).

Fig. 6
figure 6

 A forest plot shows the risk ratio of patients with dyspareunia

Full size image

Histological evaluation of vaginal atrophy

Regarding the histological evaluation of vaginal atrophy, two trials [18, 19] with a total of 115 patients in the oxytocin arm and 185 patients in the placebo arm were included in the analysis. There was a statistically insignificant decrease in the oxytocin arm over the placebo arm (MD = -0.38, 95% CI (-0.82-0.06), P = 0.09). The pooled studies were homogenous (I2 = 0%, P = 0.97) (Fig. 7).

Fig. 7
figure 7

 A forest plot shows the mean difference of change in the histological evaluation of vaginal atrophy

Full size image

Safety (endometrial thickness)

Regarding endometrial thickness, two trials [18, 19] with a total of 64 patients in the oxytocin arm and 53 patients in the placebo arm were included in the analysis. There was a statistically insignificant difference between the two arms (MD = 0.00, 95% CI (-0.23-0.23), P = 0.99). The pooled studies were homogenous (I2 = 0%, P = 0.60) (Fig. 8).

Fig. 8
figure 8

 A forest plot shows the mean difference of change in the endometrial thickness

Full size image

Discussion

This study was conducted to update the previous systematic review [13] that assessed the efficacy of intravaginal oxytocin gel on the symptoms and laboratory parameters of GSM.

Our meta-analysis showed that the administration of intravaginal oxytocin causes statistically insignificant cytological changes in the vaginal mucosa (vaginal maturation index). On the other hand, Ghorbani and Mirghafourvand [13] documented statistically significant changes because they did not consider the significant heterogeneity. The vaginal maturation index is an indicator of vaginal atrophy that measures the number of intermediate and superficial mucosal cells in relation to immature basal cells [29]. A decreased vaginal maturation index suggests increased vaginal atrophy.

The meta-analysis also showed a statistically insignificant effect of oxytocin on vaginal pH. Four studies, including Jonasson et al. (2020) [14], the newly included study, evaluated changes in vaginal pH, which is considered a valuable parameter in diagnosing vaginal atrophy in addition to the vaginal maturation index. Despite the insignificant changes in these two parameters, the meta-analysis of clinically assessed vaginal atrophy showed oxytocin causing a statistically significant decrease in vaginal atrophy. Clinically assessed vaginal atrophy, as an outcome, was only discussed in two of the old studies [14, 15]. So, the weight of its meta-analysis may not be reliable.

The deficiency of estrogen following menopause causes structural changes in the vaginal epithelium, which can cause the symptoms of GSM, such as itching, dryness, burning, dysuria, and dyspareunia [29]. Despite the importance of dyspareunia as a subjective parameter of vaginal atrophy’s effect on the quality of life of patients with GSM, it was not analyzed in the previous meta-analyses. Furthermore, the meta-analysis of dyspareunia data revealed that vaginal oxytocin does not affect dyspareunia.

Moreover, vaginal atrophy is assessed by histological evaluation, which depends on the number of layers, size of nuclei, and glycogen content of the cells rather than the number of cells in each layer [14]. Despite its high sensitivity in diagnosing vaginal atrophy, histological evaluation is invasive; therefore, it was only done in two studies [18, 19]. The meta-analysis of the histological evaluation showed that the effect of oxytocin was insignificant. The two new trials [16, 28] did not evaluate this outcome; therefore, the results were similar to the previous review. In addition, they did not update the endometrial thickness meta-analysis data, where current evidence suggests that oxytocin does not affect endometrial thickness. Furthermore, we could not perform a meta-analysis of estrogen serum levels because of the difference in measurement units between the studies. Otherwise, these studies [14, 19] found no significant effect of oxytocin on estrogen levels.

The studies included in this systematic review found no statistical evidence of oxytocin affecting either the clinical or lab-based parameters of GSM except for Zohrabi et al. (2020) [28], where a statistically significant effect on vaginal maturation index and vaginal pH was found. However, the same study caused significant heterogeneity.

Hormonal compounds (estrogen alone or estrogen with progesterone) are effective in alleviating the symptoms of GSM, but their safety is questioned [30, 31]. Therefore, it is necessary to find effective alternatives, such as oxytocin. Oxytocin receptors are expressed in various areas, including the vaginal epithelium, where oxytocin plays a role in proliferation and differentiation [32]. In vitro studies and clinical trials [12, 14, 15, 18, 19] have shown that oxytocin has promising results in GSM. In addition, it has protective effects against endometrial, ovarian, and colon cancers [33, 34], unlike estrogen, whose usage is associated with estrogen-dependent cancers [31].

This study answered questions that were not previously discussed, such as whether oxytocin affects different parameters of GSM, such as vaginal pH, vaginal atrophy, and dyspareunia. Moreover, we updated the discussion about the effect of oxytocin on vaginal cytology through the vaginal maturation index by addressing the significant heterogeneity.

Given these findings, the clinical implications of our study indicate that the use of intravaginal oxytocin as a treatment option for GSM should be approached with caution. Although oxytocin has shown promising results in preclinical studies and clinical trials, our study did not provide sufficient evidence to support its clinical efficacy in treating GSM. Clinicians should carefully consider individual patient factors, preferences, and medical history when making treatment decisions for GSM. In cases where patients cannot or prefer not to use hormonal therapy, intravaginal oxytocin may be considered as a potential alternative. However, it is important to acknowledge the limitations of our study, including the small number of trials assessing subjective symptoms and the insignificant results observed in our meta-analysis. Further research is needed to better understand the efficacy and safety profile of oxytocin in GSM management. Future studies should explore optimal dosing regimens, long-term effects, patient satisfaction, and the mechanism of action of oxytocin in GSM. Additionally, larger-scale trials with rigorous study designs and standardized outcome measures are necessary to provide more robust evidence on the clinical effectiveness of oxytocin for GSM. In summary, while our study did not find significant effects of intravaginal oxytocin on GSM symptoms and laboratory parameters, it highlights the need for further investigation. Clinicians should exercise caution and consider personalized treatment approaches for GSM patients, taking into account individual patient factors and preferences, until additional evidence becomes available.

Strengths and limitations

Our systematic review and meta-analysis have several advantages. We included all available published studies and increased the sample size by 40% over the previous study. We reported important outcomes that had not been evaluated in the previous meta-analysis, including vaginal pH, clinically assessed vaginal atrophy, and dyspareunia. Furthermore, the majority of the outcomes were homogeneous. Finally, whenever high heterogeneity was present, we investigated the robustness of our results using sensitivity analysis and random effect models.

However, the limitations of this study include the small sample size and limited number of studies included in our analyses, short and different follow-up periods, the use of various tools in each study to assess vaginal atrophy, and the use of different drug dosages. Due to data limitations, we were unable to conduct subgroup analyses to investigate the impact of the aforementioned variations. In addition, there was variation in the eligibility criteria of the clinical trials, where some studies [14, 15, 17, 28] used subjective methods such as patient-reported symptoms, whereas other studies [18, 19] used clinical and lab-based criteria for the enrollment of patients.

Conclusion

The meta-analysis results indicate that vaginal oxytocin does not have a significant effect on genitourinary syndrome of menopause (GSM) patients in terms of the vaginal maturation index, vaginal pH, histological evaluation, endometrial thickness, and dyspareunia. However, a statistically significant decrease was observed in clinically assessed vaginal atrophy. It is important to note that this study’s limitations, including the limited number of included studies and variations in treatment duration, prevent definitive conclusions from being drawn solely based on these findings.

Despite the lack of acceptance of oxytocin as a valuable alternative to estrogen in GSM, the possibility of its efficacy cannot be entirely dismissed. To address the aforementioned limitations, further rigorous clinical trials are strongly encouraged. These studies should aim to provide clearer evidence regarding the impact of oxytocin on different parameters of GSM. Only through additional research can a more comprehensive understanding of oxytocin’s effects in GSM be achieved.

Availability of data and materials

All data analyzed during this study are included in this published article or listed in references.

Abbreviations

BMI:

Body mass index

CI:

Confidence interval

FSFI:

Female Sexual Function Index

FSH:

Follicle-stimulating hormone

GSM:

Genitourinary syndrome of menopause

IU:

International unit

MD:

Mean difference

PROSPERO:

International Prospective Register of Systematic Reviews

QOL:

Quality of life

RCTs:

Randomized controlled trials

ROB:

Risk of bias

RR:

Risk ratio

References

  1. Morabia A, Costanza MC. International Variability in Ages at Menarche, First Livebirth, and Menopause. Am J Epidemiol. 1998;148:1195–205.

    Article  CAS  PubMed  Google Scholar 

  2. Santoro N, Roeca C, Peters BA, Neal-Perry G. The menopause transition: signs, symptoms, and Management Options. J Clin Endocrinol Metab. 2021;106:1–15.

    Article  PubMed  Google Scholar 

  3. Takahashi TA, Johnson KM, Menopause. Med Clin North Am. 2015;99:521–34.

    Article  PubMed  Google Scholar 

  4. Portman DJ, Gass MLS. Genitourinary syndrome of menopause. Menopause. 2014;21:1063–8.

    Article  PubMed  Google Scholar 

  5. Angelou K, Grigoriadis T, Diakosavvas M, Zacharakis D, Athanasiou S. The Genitourinary Syndrome of Menopause: an overview of the recent data. Cureus. 2020. https://doi.org/10.7759/cureus.7586.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Moral E, Delgado JL, Carmona F, Caballero B, Guillán C, González PM, et al. Genitourinary syndrome of menopause. Prevalence and quality of life in spanish postmenopausal women. The GENISSE study. Climacteric. 2018;21:167–73.

    Article  CAS  PubMed  Google Scholar 

  7. Palma F, Volpe A, Villa P, Cagnacci A. Vaginal atrophy of women in postmenopause. Results from a multicentric observational study: the AGATA study. Maturitas. 2016;83:40–4.

    Article  CAS  PubMed  Google Scholar 

  8. Nappi RE, Kokot-Kierepa M. Vaginal Health: Insights, Views & Attitudes (VIVA) – results from an international survey. Climacteric. 2012;15:36–44.

    Article  CAS  PubMed  Google Scholar 

  9. Nappi RE, Palacios S, Bruyniks N, Particco M, Panay N. The burden of vulvovaginal atrophy on women’s daily living: implications on quality of life from a face-to-face real-life survey. Menopause. 2019;26:485–91.

    Article  PubMed  Google Scholar 

  10. Szymański J, Zaręba K, Jakiel G, Słabuszewska-Jóźwiak A. Genitourinary syndrome of menopause – is the problem solved? State of the art 2018. Menopausal Rev. 2018;17:173–9.

    Article  Google Scholar 

  11. Lethaby A, Ayeleke RO, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2016;2016:CD001500.

  12. Kallak TK, Uvnäs-Moberg K. Oxytocin stimulates cell proliferation in vaginal cell line Vk2E6E7. Post Reprod Heal. 2017;23:6–12.

    Article  Google Scholar 

  13. Ghorbani Z, Mirghafourvand M. The efficacy and safety of intravaginal oxytocin on vaginal atrophy: a systematic review. Post Reprod Heal. 2021;27:30–41.

    Article  Google Scholar 

  14. Jonasson AF, Edwall L, Uvnäs-Moberg K. Topical oxytocin reverses vaginal atrophy in postmenopausal women: a double-blind randomized pilot study. Menopause Int. 2011;17:120–5.

    Article  PubMed  Google Scholar 

  15. Torky HA, Taha A, Marie H, El-Desouky E, Raslan O, Moussa AA, et al. Role of topical oxytocin in improving vaginal atrophy in postmenopausal women: a randomized, controlled trial. Climacteric. 2018;21:174–8.

    Article  CAS  PubMed  Google Scholar 

  16. Fianu Jonasson A, Bixo M, Sundström Poromaa I, Åstrom M. Safety and Efficacy of an Oxytocin Gel and an equivalent gel but without hormonal ingredients (Vagivital® Gel) in Postmenopausal women with symptoms of Vulvovaginal Atrophy: a Randomized, double-blind controlled study. Med Devices Evid Res. 2020;13:339–47.

    Article  Google Scholar 

  17. Abedi P, Zohrabi I, Ansari S, Maraghi E, Maram NS, Houshmand G. The impact of oxytocin vaginal gel on sexual function in Postmenopausal Women: a Randomized Controlled Trial. J Sex Marital Ther. 2020;46:377–84.

    Article  PubMed  Google Scholar 

  18. Al-Saqi SH, Uvnäs-Moberg K, Jonasson AF. Intravaginally applied oxytocin improves post-menopausal vaginal atrophy. Post Reprod Heal. 2015;21:88–97.

    Article  Google Scholar 

  19. Al-Saqi SH, Jonasson AF, Naessén T, Uvnäs-Moberg K. Oxytocin improves cytological and histological profiles of vaginal atrophy in postmenopausal women. Post Reprod Heal. 2016;22:25–33.

    Article  Google Scholar 

  20. Viero C, Shibuya I, Kitamura N, Verkhratsky A, Fujihara H, Katoh A, et al. REVIEW: Oxytocin: crossing the bridge between Basic Science and Pharmacotherapy. CNS Neurosci Ther. 2010;16:e138–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kirsch P. Oxytocin in the socioemotional brain: implications for psychiatric disorders. Dialogues Clin Neurosci. 2015;17:463–76.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Nielsen EI, Al-Saqi SH, Jonasson AF, Uvnäs-Moberg K. Population Pharmacokinetic Analysis of Vaginally and Intravenously Administered Oxytocin in Postmenopausal Women. J Clin Pharmacol. 2017;57:1573–81.

    Article  CAS  PubMed  Google Scholar 

  23. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. PLOS Med. 2021;18:e1003583.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Higgins JPT. In: Thomas J, Chandler J, Cumpston M, Li T, Page MJWV, editors. Cochrane Handbook for systematic reviews of interventions. 2nd Editio ed. Chichester (UK): John Wiley & Sons, Ltd; 5391.

    Google Scholar 

  25. Green S, Higgins P, Alderson P, Clarke M, Mulrow DC, Oxman DA. Cochrane Handbook: Cochrane Reviews: ch 8. Assessing risk of bias in included studies. Cochrane Handb Syst Rev Interv. 2011;1:3–11.

  26. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Review Manager (RevMan). [Computer program]. Version 5.4. The Cochrane Collaboration; 2020.

  28. Zohrabi I, Abedi P, Ansari S, Maraghi E, Shakiba Maram N, Houshmand G. The effect of oxytocin vaginal gel on vaginal atrophy in postmenopausal women: a randomized controlled trial. BMC Womens Health. 2020;20:108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gandhi J, Chen A, Dagur G, Suh Y, Smith N, Cali B, et al. Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management. Am J Obstet Gynecol. 2016;215:704–11.

    Article  PubMed  Google Scholar 

  30. Nilsson K, Risberg B, Heimer G. The vaginal epithelium in the postmenopause — cytology, histology and pH as methods of assessment. Maturitas. 1995;21:51–6.

    Article  CAS  PubMed  Google Scholar 

  31. Banks E, Beral V, Bull D, Reeves G, Austoker J, English R, et al. Breast cancer and hormone-replacement therapy in the million women study. Lancet. 2003;362:419–27.

    Article  Google Scholar 

  32. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and Regulation. Physiol Rev. 2001;81:629–83.

    Article  CAS  PubMed  Google Scholar 

  33. Peter J, Burbach H, Adan RAH, Tol HHM, Verbeeck MAE, Axelson JF, et al. Regulation of the Rat Oxytocin Gene by Estradiol. J Neuroendocrinol. 1990;2:633–9.

    Article  CAS  PubMed  Google Scholar 

  34. Cassoni P, Sapino A, Marrocco T, Chini B, Bussolati G. Oxytocin and Oxytocin Receptors in Cancer cells and proliferation. J Neuroendocrinol. 2004;16:362–4.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).

Author information

Authors and Affiliations

  1. Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt

    Ramadan Abdelmoez Farahat

  2. Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt

    Hazem Mohamed Salamah

  3. Faculty of Medicine, Minia University, Minia, Egypt

    Abdelrahman Mahmoud

  4. Faculty of Medicine, Menoufia University, Menoufia, Egypt

    Esraa Hamouda & Heba Hamouda

  5. Faculty of Medicine, Cairo University, Giza, Egypt

    Mahmoud Hashemy

  6. Faculty of Medicine, Assiut University, Assiut, Egypt

    Ali Samir

  7. Faculty of Medicine and Pharmacy, Oujda, Oujda-Angad, Morocco

    Imane Chenfouh

  8. Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Ahmed Marey & Dina M. Awad

  9. Department of Obstetrics and Gynecology, Faculty of Medicine, Alazhar University, Cairo, Egypt

    Elsayed Farag & Elsayed Eldesouky

  10. Faculty of Medicine, Fayoum University, Fayoum, Egypt

    Mohamed Abd-Elgawad

Authors
  1. Ramadan Abdelmoez Farahat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hazem Mohamed Salamah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdelrahman Mahmoud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Esraa Hamouda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mahmoud Hashemy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heba Hamouda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ali Samir
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Imane Chenfouh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ahmed Marey
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dina M. Awad
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Elsayed Farag
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mohamed Abd-Elgawad
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Elsayed Eldesouky
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.A.F. validated the idea, conducted the search and analyses, formulated the extraction sheets, drafted the tables, and took part in writing the results section. H.M.S. drafted the figures, revised the tables, took part in writing the abstract and result sections, and reviewed/edited the final version of the manuscript. A.M. took part in the two phases of screening, revised the analysis, and wrote the abstract, introduction, and methods sections. E.H. took part in the two phases of screening, data extraction, and results writing. M.H. took part in the two phases of screening and data extraction. H.H. took part in the two phases of screening and data extraction. A.S. took part in the two phases of screening and R.O.B. assessment. I.C. took part in the two phases of screening and R.O.B. assessment. A.M. wrote the discussion and conclusions sections. D.A. reviewed and edited the manuscript. E.F. reviewed and edited the manuscript. M.A.E. reviewed and edited the manuscript. E.E. formulated the research question and reviewed/edited the manuscript. All authors revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Hazem Mohamed Salamah.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

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

Supplementary Information

Rights and permissions

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/. 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 in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farahat, R.A., Salamah, H.M., Mahmoud, A. et al. The efficacy of oxytocin gel in postmenopausal women with vaginal atrophy: an updated systematic review and meta-analysis. BMC Women's Health 23, 494 (2023). https://doi.org/10.1186/s12905-023-02645-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12905-023-02645-0

Keywords

BMC Women's Health

ISSN: 1472-6874

Contact us