Estrogen and the Urogenital Microbiome in GSM

Women who have undergone menopause almost ubiquitously experience pelvic complaints at some
point in the postmenopausal period. This is most commonly vaginal dryness and discomfort
during sexual intercourse. From previous studies, we know that as estrogen levels decrease in
menopause, changes occur in the local urogenital tract that include thinning of the vaginal
epithelium, an increase in pH and an alteration of the composition of the local bacterial
community, including a decrease in the typically predominant species of bacteria
lactobacilli. In conjunction with declining estrogen levels, a subset of postmenopausal women
experience bothersome lower urinary tract symptoms such as burning with urination, urinary
urgency, incontinence and recurrent urinary tract infections. These symptoms are commonly
underreported, under-treated, and have been associated with reduced quality of life and
decreased productivity in menopause. "Genitourinary Syndrome of Menopause" (GSM) is a term
adapted to be more inclusive of these lower urinary tract symptoms in an effort to reduce
delays in evaluation and treatment. It remains controversial whether these symptoms relate
directly to estrogen deprivation or are part of the "natural" aging process. Mainstay therapy
includes vaginal lubricants and local estrogen therapy. Though treatment with local estrogen
improves both vaginal dryness as well as urinary symptoms, the mechanism is not well
understood.

Additionally, there is a subset of women who do not respond to estrogen treatment or have
contraindications to estrogen use. Recent research efforts have been exploring the potential
role that the microbiome may play in female pelvic discomfort and dysfunction. Unlike the
vagina, the bladder has historically been considered to be a sterile environment, with the
presence of bacteria implying infection. However, recent research has helped to elucidate
that, similar to the skin, vagina and gastrointestinal tract, a resident microbial community
or "microbiome" exists within the female bladder. Disturbances in the urinary microbial
community have been correlated with conditions such as painful bladder syndrome, overactive
bladder and urge urinary incontinence. These conditions have considerable symptom overlap
with those seen in postmenopausal women who are experiencing GSM and may be considered to be
on the same continuum.

Though microbiome research over the last decade has accelerated our understanding of the role
that organisms play in health and disease, the urinary microbiome remains poorly defined.
Data from ongoing research suggests that the urinary microbiome of pre- and postmenopausal
women differ, which would suggest that hormone status may play a role in maintaining the
microbial milieu. This research has helped us to better understand how the urinary microbiome
varies under normal conditions. In order to better understand the role that estrogen plays in
maintaining the bladder and vaginal flora, this study aims to characterize the effect of
local estrogen on the urinary and vaginal microbiomes (together termed the "urogenital
microbiome") in postmenopausal women.

Inclusion Criteria:

- Postmenopausal female

- Generally healthy

Exclusion Criteria:

- Known allergy or contraindications to the intervention

- Use of hormone therapy in the last 3 months

- Current tamoxifen use

- Currently using vaginal pessary

- History of breast cancer or BRCA mutation

- History of uterine, ovarian or cervical cancer

- History of deep vein thrombosis or pulmonary embolism

- History of stroke or myocardial infarction

- Known thrombophilic disorder (Protein S deficiency, Protein C deficiency, antithrombin
deficiency)

- Known liver disease

- Use of systemic or vaginal antibiotics in the last 2 months

- Urinary tract or vaginal infection in the last 2 months