By: Astraea Ballinger
Hormone Replacement Therapy (HRT) is an ongoing and important topic of conversation due to its vast untapped benefits for women and people living with uteruses. Unfortunately, due to a two decade misinterpretation of study results and black box warnings, HRT has been mostly denied as an intervention for individuals who would benefit from treatment.
In the early 2000s, prescriptions for HRT products for women and people with uteruses dropped significantly due to the FDA’s addition of black box warnings. The application of the black box warnings stemmed from a Women’s Health Initiative study that warned of a significantly increased risk of breast cancer diagnosis for those using HRT. There were many flaws within the study, including an average age of the participants being 63 years old, making the participants age group over a decade past the average age of somebody who was experiencing menopause. Additionally, the study participants were given a hormone formulation that is no longer commonly used. Thankfully, there is some newly found hope due to a recent press release from the FDA, and more recent survey findings.
Say goodbye to the Black Box Warning
According to the recent press release on November 10th, the FDA is removing the boxed warnings following a comprehensive review of the scientific literature by an expert panel. The FDA is working with companies to update language in product labeling to remove references to risks of cardiovascular disease, breast cancer, and probable dementia. The FDA is not seeking to remove the boxed warning for endometrial cancer for systemic estrogen-alone products. ²
Benefits of Hormone Replacement Therapy (HRT)
- Randomized studies show that women who initiate HRT within 10 years of the onset of menopause (generally before age 60) have a reduction in all-cause mortality and fractures.
- FDA-approved HRT containing estrogen and progesterone (or estrogen alone as indicated for postmenopausal women without a uterus) can restore declining hormones, and relieve symptoms such as hot flashes, night sweats, sleep disturbances, and bone loss.²
- Estrogen is a key hormone for women and people with uteruses’ health. Every single part of the body depends on estrogen to operate at optimal levels—including the brain, bones, heart, and muscles.
- Women and people with uteruses reduce their risk of: cardiovascular diseases by as much as 50%, Alzheimer’s disease by 35%, and bone fractures by 50 to 60%.
- Estrogen also helps collagen production, and collagen disappears from the vulva by up to 30% in the five years after menopause. ³
- It’s safe for most breast cancer patients, too, and it’s a win-win on the physical intimacy front.
- You can take it alongside normal HRT.³
There are currently 7 FDA-approved vaginal estrogen products for the treatment of GSM: creams (Estrace® estradiol, Allergan, Madison, NJ; Premarin® conjugated estrogens, Pfizer, New York, NY; generic estradiol cream 0.01%), tablets (Vagifem® estradiol, Novo Nordisk Inc., Plainsboro, NJ; Yuvafem® generic estradiol, Amneal Pharmaceuticals, Bridgewater, NJ), inserts (Imvexxy® estradiol capsule, TherapeuticsMD, Inc., Boca Raton, FL), and a ring (Estring®, Pfizer). Shared decision making with the patient for choice of vaginal estrogen product is important and can improve compliance with therapy. ¹
More upcoming approvals for HRT
In addition to the removal of boxed warnings, the FDA is also approving two new drugs to expand treatment options for menopausal symptoms. The first is the approval of a generic version of Premarin (conjugated estrogens), the first such approval in more than 30 years for this widely used form of hormone replacement therapy. The new generic product is expected to improve affordability and access while maintaining the same quality, safety, and effectiveness as the brand-name drug.
The second approval is for a non-hormonal treatment for moderate to severe vasomotor symptoms, such as hot flashes, associated with menopause. This option provides relief for women who cannot or choose not to use hormone therapy. ²
HRT and Urinary Tract Infections
More than half of people with uteruses will have at least one UTI in their lifetime. One in four women and people with uteruses have a UTI strain resistant to certain common antibiotics. Younger women and people with uteruses do suffer from infections, dehydration and post-sex cystitis, but the brunt is borne by older women. UTI rates shoot upwards when women hit 45 and are perimenopause. Plus, lack of estrogen means the lactobacilli and other good bacteria in the vaginal microbiome are at risk of being replaced by pathogenic ones.
SGLT-2 Reduction of UTI with estrogen
Estrogen deficiency after menopause is an important predisposing factor for reoccurring UTIs (r UTI). Another recent study in 2020 was designed to observe the risk and frequency of UTI due to SGLT2 Inhibitors among post-menopausal individuals with T2DM and the preventive effect of vaginal e HRT for r UTI among them.
Study Design: Forty-two, post-menopausal individuals with type 2 diabetes, using vaginal e HRT were selected as cases whereas controls were 38 matched individuals not using e HRT. Subjects in both groups were prescribed SGLT2 I considering eligibility and simultaneously adjusted the doses of other OHA’s or insulin to maintain the glycemic targets. They were targeted to follow for 12 months and evaluated periodically for symptomatic UTI and maintenance of glycemic targets. Diagnosis of symptomatic UTI was made using standard definition and guidelines.
The results? The 42 participants who were using vaginal e HRT compared to the 38 who did not use e HRT, demonstrated significantly lesser frequency of UTIs. Estrogen HRT after menopause significantly reduces the frequency of UTI among people with type 2 diabetes using SGLT2 I. Or said in another way, not using eHRT for those with diabetes on SGLT-2I may significantly increase risk of complicated UTI.¹
Genitourinary Syndrome of Menopause (GSM)
The estrogen hormone deficiency associated with menopause has been renamed Genitourinary Syndrome of Menopause (GSM). This describes the chronic decrease in estrogen levels, resulting in a combination of genital, sexual, and urinary symptoms. While most common after menopause, GSM can affect premenopausal women experiencing low estrogen levels due to other medical conditions or treatments. This syndrome is associated with the hormone estrogen leaves the vulva dry in menopause (and sometimes post-pregnancy), a condition previously called “vaginal atrophy.”
Case Study Highlighting HRT Benefits for GSM
In a recent 2020 case study, a 64-year-old woman (MS) was referred for recurrent urinary tract infections (UTIs). She presented with progressive complaints of vaginal dryness, sensitivity, and pain at the introitus with associated dyspareunia despite the use of over-the-counter vaginal lubricants. MS was offered treatment with vaginal estrogen therapy for her GSM.
For relief, MS was initiated on a 2-week course of nightly estradiol cream followed by maintenance therapy twice weekly. She returned for a 3-month follow-up and reported significant improvements in vaginal dryness, with resolution of her introital irritation and dyspareunia. She had not had a UTI in this time frame. MS also reported significant improvements in her quality of life and sexual function. 4
Both the lower urinary tract in women and the vaginal and introital tissues are rich in estrogen receptors. We can prevent GSM in perimenopause and menopause by giving individuals a safe, low dose of vaginal estrogen, which plumps the tissue, feeds the vaginal microbiome and reduces UTIs by 50%.²
Effective care of women and people with uterus’s is enhanced by gaining knowledge and being aware of current recommendations for treating both menopausal symptoms in general and GSM. 4
As healthcare professionals caring for people with diabetes, we can discuss the benefits for HRT for individuals in perimenopause and menopause. We can also advocate for use of vaginal estrogen for individuals experiencing frequent UTIs, especially for those taking SGLT-2 inhibitors.
References
- ASHISH GAUTAMPRABHAT K. AGRAWALNIKHIL PURSNANIRUCHI RANI; 140-LB: Effect of Vaginal Estrogen as Hormone Replacement Therapy for Menopause on SGLT2 Inhibitor–Associated Urinary Tract Infection: A Prospective Cohort Study. Diabetes 1 June 2020; 69 (Supplement_1): 140–LB. https://doi.org/10.2337/db20-140-LB
- FDA. (2025, November 10). HHS advances women’s health, removes misleading FDA warnings on hormone replacement therapy. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/hhs-advances-womens-health-removes-misleading-fda-warnings-hormone-replacement-therapy
- Muir, K. (2023, December 17). “Millions of women are suffering who don’t have to”: Why it’s time to end the misery of UTIs. The Guardian. https://www.theguardian.com/society/2023/dec/17/millions-of-women-are-suffering-who-dont-have-to-why-its-time-to-end-the-misery-of-utis
- Rosenblum, N. (2020, December). Update in female hormonal therapy: What the urologist should know: NYU case of the month, December 2020. Reviews in urology. https://pmc.ncbi.nlm.nih.gov/articles/PMC8058921/
