This study was conducted to update the previous systematic review [13] that assesses 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 [25]. 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 vaginal atrophy showed oxytocin causing a statistically significant decrease in vaginal atrophy. 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 dependable.
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 [25]. Despite the importance of dyspareunia as a subjective parameter of vaginal atrophy 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, 24] 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 the 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 the lab-based parameters of GSM except for Zohrabi et al. (2020) [24], 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 [26, 27]. 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 [28]. In vitro studies and clinical trials [9, 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 [29, 30], unlike estrogen, whose usage is associated with estrogen-dependent cancers [27].
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.
Limitations
The limitations of this study include 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. In addition, the variation in the eligibility criteria of the clinical trials where some studies [14, 15, 17, 24] used subjective methods such as patient-reported symptoms, whereas other studies [18, 19] used clinical and lab-based criteria for the enrollment of patients.