Problems addressed by the study:
Genitourinary syndrome (GUS) is a common disorder during menopause, reported to be at
least 50% in many series, which reduces quality of life. Unfortunately, despite being
such a common disorder, patients do not report their complaints about this issue and
clinicians do not question patients about this condition (NAMS, 2020). There is little
awareness about the subject and relatively few studies on the pathophysiology and
treatment of the disease.
GUS is diagnosed clinically. Symptoms such as vulvovaginal dryness, burning or
irritation; dyspareunia; and symptoms such as urge incontinence, dysuria or recurrent
urinary tract infections are observed in the urinary system (NAMS, 2020). Urinary
symptoms of GUS, such as dysuria, are often confused with recurrent urinary tract
infections. The pathophysiology of GUS is often attributed to estrogen deficiency, but
some researchers suggest that these changes may also be related to the vaginal microbiome
(Hummelen et al., 2011). Because while estrogen deficiency is present in all women who
enter menopause, GUS is observed in a certain portion. Therefore, our study will
contribute to the literature aimed at shedding light on the pathogenesis.
Although there are both vaginal and urinary symptoms in GUS, the most studies are on
vaginal microbiota. There is only one study on urinary microbiota (Lillemon et al.,
2022). There is no study evaluating the periurethral microbiota.
Is there a relationship between vaginal microbiota and GUS symptoms?
The relationship between vaginal microbiota and GUS has been addressed in many studies.
Various changes occur in the vaginal flora during menopause due to the decrease in
estrogen hormone during menopause. Gustafsson et al. (2011) reported that women of
reproductive age were more frequently colonized with L. crispatus compared to menopausal
women. Similarly, premenopausal women had significantly higher free glycogen levels and
higher Lactobacillus levels compared to postmenopausal women (Zhang et al., 2012;
Mirmonsef et al., 2014).
Studies on patients with GUS symptoms have shown that women with mild GUS symptoms were
more likely to be predominantly Lactobacillus species in the vagina and had lower
bacterial diversity, whereas in more severe GUS cases, colonization with Lactobacillus
species was reduced and there was greater bacterial diversity (Brotman et al., 2018).
Species detected in the group with increased bacterial diversity included Prevotella,
Porphyromonas, Peptoniphilus and Bacillus (Brotman et al., 2018). Notably, CST IV-A
colonization was more prevalent in the vagina in women with the most severe GUS symptoms
(Hummelen et al., 2011, Brotman et al., 2018).
In the studies summarized here, a vaginal microbiota dominated by Lactobacillus species
was detected in all women receiving hormone replacement therapy or local estrogen
therapy, suggesting that estrogen levels have an effect on the vaginal bacterial
community and structure. However, whether GUS symptoms are reduced by estrogen-related
changes or by changes in the vaginal flora is still controversial. Although many studies
have shown that Lactobacillus dominance in the vaginal microbiota is negatively
associated with GUS symptoms, studies have recently been published showing that this is
not the case. Mitchell compared 3 groups given local estrogen, vaginal lubricant, and
placebo in their study (Mitchell, 2018). GUS complaints decreased in all three of these
groups; vaginal estradiol -1.4 (95%CI, -1.6 to -1.2); moisturizer, -1.2 (95%CI, -1.4 to
-1.0); and placebo, -1.3 (95%CI, -1.5 to -1.1). Although the amount of Lactobacilli
increased significantly in the local estrogen group compared to the other groups, the
similar decrease in complaints cannot be explained by both estrogen and microbiota
hypotheses.
We planned to use 2 different control groups in our study to investigate this issue.
Patients without any GUS symptoms and without vulvovaginal atrophy findings on
examination will be the first control group, and patients without complaints but with
vulvovaginal atrophy findings on examination will be the second control group. Examining
whether there is a difference in colonization in these two groups will be the first in
the literature and will contribute to the literature in terms of elucidating the
pathogenesis.
As mentioned before there are both vaginal and urinary symptoms in GUS. So is there a
relationship between vaginal microbiota and periurethral and urinary microbiota? There is
a study on this subject that examined both vaginal and urinary microbiota. In the study,
local estrogen treatment neither caused a significant decrease in GUS symptoms nor caused
a change in vaginal and urinary microbiota (Lillemon et al., 2022). In this study,
Lillemon and his team examined the effect of local estrogen treatment on vaginal and
urinary microbiota separately and did not examine whether there were similarities or
differences between the two environments. In addition, since they included patients who
were generally in menopause and not those with only GUS complaints in the study, local
estrogen treatment was found to be unsuccessful. Yet, local estrogen treatment is the
first-line treatment after lubricants in GUS and is a successful treatment method in 85%
of patients (NAMS, 2020). Since they used a general menopausal population in the study,
there may not have been a significant difference in microbiota between patients taking
estrogen and those not taking it, and a significant decrease in GUS complaints in those
taking local estrogen.
There is no study comparing vaginal microbiota with periurethral microbiota in GUS.
However, there is a study which compares the periurethral and urinary microbiota of women
of reproductive age that showed that both environments change after menstruation and
intercourse, and as a result, these environments are dynamic and variable like the
vaginal microbiota (Price, 2020). Again, urinary, periurethral, vaginal and fecal
microbiota were examined in women of reproductive age, urinary microbiota was compared
with fecal, and urinary microbiota was shown to be more variable compared with fecal
microbiota. However, no comments were made about vaginal and periurethral microbiota in
this study (Biehl, 2022). Therefore, our study will be the first to compare these 3
environments in GUS.
Why is periurethral microbiota important?
When we examine the GUS complaints of patients, the situation they describe as pain
during intercourse is mainly the pain they feel at the entrance to the vagina, in the
introitus. Since this area is close to the skin, we think that bacterial colonization may
be different from vaginal colonization. In this patient group, the introitus is generally
observed to be more red during examination. This also suggests that aerobic vaginitis
agents are more intense in this area. Waetjen has shown in his latest study that there is
a density of Streptococcus in the vaginal microbiota of patients with dyspareunia
(Waetjen, 2023).
Our hypotheses in this study are: 1-there is a relationship between the
vaginal-periurethral and urinary microbiota. 2- Lactobacillus colonization increases in
areas outside the vagina with local estrogen treatment. 3- The severity of GUS symptoms
is higher in patients with a microbiota predominant by facultative anaerobic bacteria
such as Staphylococcus or Streptococcus.
