Hi everyone,

As the clinical conversations around hormone therapy include both safety as well as long-term health optimization, two topics are dominating the debate this month. Both ask the same fundamental question: Are the prescriptions and endpoints we default to actually capturing what matters most for long-term health? One discussion centers on whether "symptom relief" and "adequately dosed" are truly interchangeable when it comes to long-term bone protection on MHT. The other looks at new outcomes data for recurrent UTIs, suggesting that our threshold for prescribing vaginal estrogen should be radically expanded.

✔️ A retrospective analysis of approximately 2 million women found that prescribing vaginal estrogen within 2 months of a second UTI was associated with lower rates of sepsis, hospitalization, and death across all age groups. However, only 5% of eligible women received treatment in that window.

 ✔️ A new synthesis bridging short-term transdermal gel trials with KEEPS and ELITE data proposes that serum estradiol around 60 pg/mL as optimal for bone and cardiovascular health, not just symptom relief. However, debates spark regarding the validation of the threshold itself as an inferred estimate, not a validated target.

Question for the community: Do you ever prescribe vaginal estrogen preventatively for UTIs, or only when the patient has symptoms of GSM?:

Hormone therapy is dominating clinical conversations right now, but critical nuance is frequently lost, especially regarding the pharmacokinetic and safety differences between systemic and localized therapies. Localized vaginal estrogen is often unfairly lumped into the same “contraindication bucket” as systemic MHT, so patients are often missing out on the of our most effective preventative tools.

We see this gap in practice. Patients with recurrent UTIs, or those with a personal history of breast cancer, are routinely told vaginal estrogen is off the table. Instead of addressing the root cause (urothelial thinning and loss of lactobacilli driven by estrogen deficiency), they are trapped in a cycle of repeat antibiotics. Low-dose vaginal estrogen avoids first-pass liver metabolism, maintains serum estradiol within normal postmenopausal ranges, and does not carry systemic risks. It is incredibly safe.

Untreated Genitourinary Syndrome of Menopause leaves patients exposed to repeated systemic infection risk [2]. Current guidelines already champion vaginal estrogen as a preventative option for postmenopausal women with recurrent UTIs as a reflection of meta-analysis demonstrating up to a 58% reduction in UTI recurrence [3,4,5,6].

But a massive new retrospective study expands on this, asking a bigger question: Does rehabilitating the tissue prevent severe, downstream complications?

Tracking nearly 2 million women over eight years following a second UTI, the study revealed a striking contrast. Women who were prescribed vaginal estrogen within two months of their second UTI experienced significantly lower rates of sepsis, hospital admission, and mortality compared to non-recipients. The relative risk reduction for these severe adverse events ranged from 40% to 80% across all age groups. Mortality alone was approximately 5-fold lower in the 40–69 age group, the exact demographic bearing the brunt of the menopausal transition and systemic estrogen depletion.

Figure 1. Across all age groups, vaginal estrogen recipients experienced lower rates of sepsis, admission and death compared with nonrecipients.

While the findings are compelling, maybe the most interesting point from the study isn't the mortality reduction - but the prescribing rate. Only 5.3% of eligible women with recurrent UTIs received a vaginal estrogen prescription within that critical two-month window. Across the full Epic Cosmos dataset, only 25% ever received one.

The Nuance & Limitations

As an observational dataset, we have to look at these massive risk reductions through an academic lens:

Healthy-Prescriber Bias: The researchers identified that it is possible that a vaginal estrogen prescription serves as a marker of higher-quality, proactive care or better healthcare access, rather than being the sole causal driver of reduced mortality.

Unmeasured Confounders: The study could not adjust for individual confounders, confirm medication adherence, or assess UTI severity and prior antibiotic history.

Coding Limitations: The data relied heavily on EMR coding accuracy and could not account for undocumented or compounded vaginal estrogen use.

Premenopausal Cohorts: While younger women (under 40) also showed reduced hospital admissions, this may be skewed by pregnancy-related admissions rather than UTI severity. The clinical rationale for vaginal estrogen remains firmly rooted in the postmenopausal demographic.

​The Clinical Takeaway

This study might not be enough to confidently say that vaginal estrogen alone prevents sepsis and death, but the clinical signal is strong nevertheless. We have a highly effective, localized, safe treatment to prevent recurrent UTIs, yet we are not using it often enough. Currently, vaginal estrogen comes in creams, inserts and rings.

Closing this gap requires translating that evidence into everyday clinical practice, and that’s at the core of Dama Assist. While the evidence supporting localized vaginal estrogen continues to grow, applying that data in practice, especially amidst outdated safety warnings and complex patient histories, can cause hesitation. Dama Assist acts as an on-demand clinical thinking partner, instantly surfacing the most up-to-date research and current guidelines.

Give this patient case a go and see how Dama Assist can support your decision making in real time.

Copy & paste this prompt: I'm seeing a 76-year-old postmenopausal patient with a history of DVT (provoked by surgery 10 years ago). She has had 4 UTIs in the last year, one of which resulted in a brief hospital admission. I always prescribe her antibiotics. Is there anything else I can prescribe to prevent recurrent UTIs? Given her age and VTE history, is vaginal estrogen a safe option? What does the evidence say?

Titrating MHT doses based on symptoms only, or taking into account serum levels needed for bone health?

The 2022 Menopause Society guidelines explicitly state that routine serum hormone testing is rarely needed, emphasizing instead that hormone therapy should be individualized. Yet, despite the shift toward prescribing the "appropriate dose, duration, regimen, and route," clinical practice often defaults to the historical "lowest effective dose for the shortest duration" approach, which heavily anchors on the resolution of vasomotor symptoms (VMS).

The Bone Health Blind Spot?

​​What often gets lost in a purely symptom-driven approach is the silent skeletal decline that accelerates with estrogen deprivation. A comprehensive 2024 meta-analysis in Osteoporosis International (n=49,659) found that VMS severity is a direct clinical marker for concurrent skeletal decay. Women experiencing VMS have a 54% higher risk of low bone mineral density compared to asymptomatic women, substantially increasing their fracture risk [7]. The consequences are severe; recent longitudinal data shows that postmenopausal women who accumulate three or more fragility fractures face a 2.2-fold higher mortality rate [8]. For many, a patient whose hot flashes have resolved is generally considered adequately dosed. However, a dose that stops vasomotor symptoms, is not always the same dose that protects bones long term.

A recently published synthesis attempted to bridge this gap by comparing pharmacokinetic data from two newer 12-week transdermal gel trials (focused on VMS relief) against the 4-year longitudinal KEEPS and ELITE trials. In the gel trials, the 1.25g dose produced a median serum estradiol of 32.0 pg/mL, comparable to standard low-dose transdermal patch arms. The 2.5g gel dose produced a median estradiol of 60.0 pg/mL, which was more strongly associated with optimal VMS control. The study highlights that serum levels above 60 pg/mL are associated with effective bone protection in 95–100% of women, implying that levels below this threshold leave women vulnerable to significant bone loss.

​However, this 60 pg/mL threshold is an inferred target derived from cross-referencing the VMS dose-response in the short-term gel trials, systemic outcomes in KEEPS and ELITE, and historical modeling on estradiol and bone preservation. This interpretation potentially overstates biomarker improvement vs clinical outcomes.

​Historical modeling shows that while levels above 60 pg/mL are required to fully suppress biochemical markers of bone resorption in nearly all women [9], many women achieve highly effective clinical bone preservation at much lower serum levels (e.g., 20–40 pg/mL) [10]. This is why the FDA approved transdermal patches (delivering just 14 mcg/day and yielding serum levels around 15–25 pg/mL) specifically for osteoporosis prevention [11].

The reality is that whether a patient experiences bone loss depends heavily on her compounded clinical risk profile, including resistance training, calcium and vitamin D status, and genetic predisposition, rather than a strict serum estradiol cutoff alone. Furthermore, the clinical trade-off is that pushing levels higher than 60 pg/mL to guarantee universal suppression of resorption markers does not necessarily equate to continually increasing bone density. Instead, it may increase the risk of dose-dependent estrogenic side effects, such as breast tenderness.

Cardiovascular Nuance

When it comes to cardiovascular health, the trials are more nuanced. The KEEPS trial compared oral conjugated equine estrogens (0.45 mg/day) and transdermal estradiol (0.05 mg/day patch) head-to-head with a placebo in recently menopausal women. KEEPS found significant improvements in bone mineral density and symptom control, but it did not show a reduction in the progression of carotid intima-media thickness (CIMT), a surrogate marker for atherosclerosis, over the 4-year period. While neither regimen reduced the CIMT, KEEPS did reveal distinct route-specific metabolic benefits. Oral CEE significantly improved standard lipid profiles (lowering LDL-C and increasing HDL-C), whereas transdermal estradiol significantly improved insulin sensitivity and glucose metabolism.

In contrast, the ELITE trial compared 1 mg/day of oral 17β-estradiol with a placebo, stratifying participants by time since menopause. ELITE found a significant slowing of CIMT progression specifically when treatment was initiated within six years of menopause, with optimal effects noted when serum estradiol levels reached 57 pg/mL. Furthermore, secondary analyses of ELITE showed that higher attained serum estradiol levels strongly correlated with favorable changes in lipid profiles (reducing LDL-C and atherogenic particles). Importantly, these metabolic and lipid improvements were observed in both early and late menopausal cohorts [12].​ 

Importantly, these are surrogate markers, not hard cardiovascular and cardiometabolic outcomes. Neither KEEPS nor ELITE demonstrated a reduction in myocardial infarction or stroke, nor did ELITE find a significant effect on cardiac CT measures of coronary artery calcium, total stenosis, or plaque volume. The observed early-initiation CIMT benefit cannot be fully extrapolated to the prevention of cardiovascular disease events and can’t be fully generalized.

The pharmacokinetic issue when comparing oral regimen and gels

​The bridging method used to equate transdermal gel pharmacokinetics to KEEPS and ELITE presents a limitation. Comparing transdermal gel estradiol profiles directly against oral regimens is simplistic because the two routes are metabolized entirely differently. Oral estrogen undergoes extensive hepatic first-pass metabolism, which profoundly alters the estradiol-to-estrone ratio, stimulates hepatic protein synthesis, and alters sex hormone-binding globulin (SHBG), consequently impacting lipid profiles and clotting factors. Achieving a 60 pg/mL serum estradiol level via transdermal gel bypasses this hepatic mechanism, meaning its long-term cardiometabolic effects cannot be assumed to identically mirror the outcomes of the oral regimens utilized in ELITE.

Figure 2.​ Oral (Left) versus transdermal routes (Right) of administration of oestradiol-based menopausal hormone therapy.

Transdermal Variability and Tissue Receptors

Different estradiol formulations possess distinctive physicochemical properties that influence absorption rates. Interindividual absorption and bioavailability are heavily influenced by numerous variables:

• Patient factors: Age, ethnicity, BMI, skin adiposity, hydration, capillary density, baseline SHBG, and body temperature.

• Dermatological factors: Absorption may increase in individuals with inflammatory skin conditions like eczema. Up to 20% of patch users report local skin reactions that can either reduce adhesion (decreasing absorption) or increase skin permeability (increasing absorption).

• Application variables: The site of application (e.g., abdomen vs. buttock), manufactured delivery method, and concurrent use of other topicals [13].

The Clinical Bottom Line

All in all, the 60 pg/mL target is an evidence-informed estimate, not a universally validated threshold. The ultimate driver of clinical effect is having sufficient estradiol to impact estrogen receptors at the tissue level; serum levels are merely a proxy. Because estrogen receptor density and sensitivity differ substantially between individual women, a serum level of 40 pg/mL might fully saturate the bone receptors in one patient, providing 100% protection, while another patient might have less sensitive receptors and require 60 pg/mL to achieve the exact same effect. For patients with high fracture risk, assess bone health clinically (via DEXA and FRAX), consider targeted osteoporosis pharmacotherapy if indicated and encourage the patient to take on lifestyle interventions like resistance training alongside their MHT.

Standard dose equivalence charts rarely account for first-pass metabolism and transdermal absorption variability. As a result, switching a patient’s MHT formulation can easily result in unintended under-dosing or over-dosing. Closing that gap is exactly why we built the Advanced MHT Bioequivalency and Absorption Tool inside the Dama Assist platform. Now, rather than relying on guesswork, you can:

• Evaluate Absorption: Enter a patient's measured serum estradiol alongside her current formulation to see how she compares to expected population exposure.

• Convert with Confidence: Find a genuinely comparable medication based on rigorous pharmacokinetic data (AUC/Cmax) when you need to switch delivery routes.

Want to try the Advanced MHT Bioequivalency & Absorption Tool? Sign up for your free two week trial directly here: https://www.damaassist.com/

Conclusion

This month’s research reminds us to think beyond short term symptom resolution to long term health outcomes and take a second look at our "asymptomatic" patients. A patient with a history of recurrent UTIs and has been treated with antibiotics but never been offered vaginal estrogen may be carrying a much heavier downstream risk of hospitalization. Similarly, a patient whose vasomotor symptoms have resolved may not be automatically protected against bone loss.

Until next month!
-- The Dama Health Team