The Dama Newsletter: Trending conversations in September

Hello everyone,

Navigating midlife hormone management increasingly requires balancing strict guidelines with rapid shifts in patient demand. Consider two common presentations in clinic today: a 50-year-old woman requesting compounded testosterone, and a perimenopausal patient experiencing severe "brain fog" who is asking about novel interventions like estriol. In both scenarios, clinicians are caught in the gray area between biological plausibility, evolving evidence, and regulatory gaps. We are all thinking about how to best bridge the gap between guidelines and the real-world drive for health optimization. This month, we are breaking down two major developments shaping this landscape: the latest FDA public workshop on female testosterone prescribing and preliminary data evaluating estriol for cognitive function.

TL;DR

✔️ Testosterone FDA panel: The FDA recently hosted a public workshop on testosterone prescribing in women’s health. While testosterone has proven efficacy for Hypoactive Sexual Desire Disorder (HSDD), data regarding long-term safety (cardiovascular and breast cancer risks) remain inconclusive. Current studies are limited by methodological heterogeneity, variable formulations, and a lack of longitudinal safety data beyond 24 months. Without this long-term data, FDA approval remains stalled, forcing clinicians to navigate off-label and compounded prescribing.

✔️ Estriol for Brain Fog: Early proof-of-concept data suggest estriol may help resolve menopausal "brain fog" by reducing cellular neuroinflammation, but study limitations and small sample sizes call for large-scale RCTs before comparing its efficacy to standard estradiol.

The FDA Testosterone Workshop

Here’s what you need to know about HSDD, CVD, and Breast Cancer.​The United States lacks an FDA-approved female testosterone formulation. For evidence-based indications like HSDD, this forces clinicians to navigate a challenging prescribing landscape, relying either on titration of male products or turning to compounded pharmacies. This lack of a dose-appropriate, FDA-approved formulation increases the risk of variable absorption, supraphysiologic dosing, and subsequent androgenic adverse events, underscoring the need for a regulated female-specific product in the US. To begin addressing this issue, the FDA hosted a public workshop this month. Currently, the clinical practice remains anchored by the Global Consensus Position Statement in 2019 on testosterone prescribing in women. This statement analyzed data from over 8,000 post-menopausal women across randomized controlled trials and concluded that the clinical evidence differs significantly across endpoints. However, past regulatory applications have stalled because Phase III trials either failed to beat placebo for sexual and desire endpoints, or were halted before they could establish the long-term (> 24 month) cardiovascular and breast cancer safety data the FDA requires for approval. In this edition, we'll focus on the evidence as it stands regarding HSDD, cardiovascular health, and breast cancer.

Efficacy in HSDD

Currently, HSDD in postmenopausal women is the only indication for testosterone therapy in the US. The foundational data for this stems from pivotal RCTs, notably the Intimate SM 1 study and APHRODITE trials, which evaluated the efficacy of a 300 mcg/day transdermal testosterone patch.

These trials demonstrated a clinical benefit. Rather than just a general "increase in libido," the data showed significant improvements across the defining triad of HSDD. Women randomized to the 300 mcg/day dose experienced an average increase of 2.1 satisfying sexual episodes per 4-week period. Alongside the increase in sexual episodes, these women reported statistically significant increases in baseline sexual desire and decreases in associated personal distress.

However, this proven efficacy must be weighed against safety and tolerability limitations. The APHRODITE trial noted higher rates of androgenic adverse events at the 300 mcg dose, primarily unwanted hair growth (30.0% compared to 23.1% on placebo). More critically, these trials highlight why long-term safety data remain inconclusive (which we will detail below). These signals underscore exactly why regulatory bodies hesitate to approve a product without definitive, multi-year safety outcomes beyond the 24-month mark.

Long-Term Endpoints

Cardiovascular health
The presenters highlighted two key observational studies with contrasting results: the UK Database (GPRD/THIN) and the TriNetX study.

• The UK Database showed a 2-fold increase in ischemic heart disease after 6.7 years of use, but the women used methods that are not routinely used in modern clinical practice (e.g., oral testosterone undecanoate, intramuscular testosterone enanthate and propionate, testosterone implants, and mesterolone). Additionally, the doses were not documented, and the testosterone users were more likely to use MHT concurrently, making it difficult to isolate the effects of testosterone.
• Conversely, the TriNetX study suggested a lower risk of major atherosclerotic cardiovascular events (MACE) in women under 56 and a neutral effect in women aged 56 and older using injectable or topical testosterone (and not oral synthetics). While MACE itself remains debated as a hard clinical endpoint, due to the combination of fatal and non-fatal events, the observational nature of this study prevents the ability to draw causal conclusions. Furthermore, these results are likely heavily skewed by a "healthy user bias" as women seeking and receiving testosterone tend to be healthier, more proactive about their metabolic health, and have greater access to care.

The Lopez et al. (2023) Data & The Transgender Comparison
Interestingly, the speakers at the FDA workshop did not present a recent observational study (Lopez et al., 2023) reported a 24% increased risk of overall CVD, a 26% increased risk of coronary artery disease, and a 29% increased risk of stroke in cisgender women over 30 years of age taking testosterone (tracked by prescription records and injection counts). No statistically significant increased risk was reported amongst transgender individuals, but this subgroup included only 1,580 individuals, which was underpowered compared to the 25,796 cisgender women analyzed. Ultimately, the observational evidence remains contradictory, especially in application to modern formulary and method prescribing preferences.

In response to this, some advocates argue that we do have long-term safety data from the transgender population using supra-physiologic testosterone doses. However, while transgender data is highly valuable and provides reassuring longitudinal insights, it cannot be perfectly extrapolated to peri- and postmenopausal cisgender women who are currently prescribed off-label, compounded formulations.

✔️ Recently completed trial (unpublished): Monash University recently presented preliminary, double-blind, placebo-controlled RCT data at the Australasian Menopause Society Congress. In a double-blind, placebo-controlled, randomized cross-over trial, Women over 55 received 4 months of testosterone or placebo to evaluate functional and structural cardiac changes. Top-level results demonstrated no improvement in maximal oxygen capacity, quality of life, or assessments of heart and muscle function compared to placebo. While an exploratory analysis revealed a small increase in left ventricular mass in the testosterone group, it was not deemed a clinically validated cardiac effect. Although this analysis is preliminary, it was a short, 4-month trial evaluating surrogate markers, not long-term cardiovascular events. Therefore, the evidence does not currently favor a cardiovascular benefit from testosterone use in menopausal women, nor does it prove a causal negative effect when used at female physiologic doses. We hope to critically evaluate this study once it is fully published in the coming months.

✔️ The Safety Data Ceiling: Ultimately, the primary roadblock to an FDA-approved female product is the insufficient long-term safety data beyond 24 months for physiologic doses of testosterone, specifically related to cardiovascular, breast and endometrial cancer risk. While the LibiGel BLISS trial was intended to be a 5-year cardiovascular safety study in 3,500 women, it was halted after four years due to funding limitations, leaving a permanent gap in long-term regulatory data.

Breast Cancer
Mechanistically, concerns regarding breast cancer risk stem from observational studies that consistently link higher circulating endogenous testosterone levels in women with a higher baseline risk of breast cancer. The leading theory revolves around aromatization, specifically that testosterone converts into estradiol within breast tissue, potentially stimulating cellular proliferation. This correlation makes a potential risk between testosterone levels and breast cancer biologically plausible.

In the previously discussed APHRODITE trial evaluating testosterone for libido, there were 4 cases of breast cancer in the testosterone patch group compared to 0 in the placebo group. However, further review of those cases revealed that at least two of them were pre-existing.

Broader observational data on exogenous testosterone use and breast cancer remains limited and dependent on the formulation studied. The Nurses’ Health Study and the WHI showed an increased risk (or a trend toward, in the case of the WHI study) of breast cancer when oral methyltestosterone was combined with esterified estrogens. Ultimately, it remains inconclusive whether the observed breast cancer risk was driven by the synthetic testosterone itself, the concurrent oral estrogen, or the combination of both. Conversely, the aforementioned UK GPRD and TriNetX databases showed no increased risk of breast cancer, though both studies carried their methodological limitations as previously described.

A 2018 systematic review of 117 publications concluded that “the use of transdermal testosterone to treat HSDD in postmenopausal women does not increase breast cancer incidence.” However, the included trials were too heterogeneous to perform a meta-analysis, and no head-to-head comparisons between administration methods have been conducted to date.

Therefore, there is insufficient long-term and high-quality data to suggest whether testosterone has a clinically protective, neutral, or detrimental risk for breast cancer in menopausal women.

Clinical Pearls

✔️ HSDD is currently the only indication (but clinical reality is nuanced): According to the 2019 Global Consensus and the 2023 Menopause Society guidelines, Testosterone has Level 1 evidence (i.e., clinically relevant evidence) for treating HSDD. However, there is insufficient RCT evidence to support its benefits in non-sexual endpoints.

✔️ The 24-month safety data ceiling: Currently, RCTs do not extend beyond 24 months and excluded high-risk cardiometabolic patients, meaning the long-term cardiovascular and breast cancer risks of testosterone therapy in women remain unknown.

✔️ Rethink standard blood testing: Standard immunoassays are likely inaccurate and unreliable for female physiologic levels (often <50 ng/dL). Use LC-MS/MS testing to establish a baseline and ensure a level that is not driving a woman into supra-physiologic ranges.

Estriol for Brain Fog

Cognitive symptoms, often described by patients as "brain fog," memory lapses, and reduced processing speed, are among the most disruptive and debilitating complaints during the menopausal transition. The severity of these symptoms frequently leads women to legitimately worry about early-onset Alzheimer's. To help clinicians validate these experiences while providing evidence-based reassurance, the International Menopause Society (IMS) differentiates menopausal cognitive shifts from dementia by highlighting three key points: (1) true dementia before age 64 is exceedingly rare (affecting less than ~0.3% of women globally); (2) unlike dementia, higher-order executive functions generally remain intact; and (3) menopausal brain fog represents a neuroendocrine transition rather than a progressive disease, primarily manifesting as specific, targeted deficits in verbal learning, word-finding, and processing speed.

A new study out of UCLA Health suggested a customized regimen of estriol (a patented product of UCLA named PearlPAK) and progesterone may ease these cognitive symptoms.​​

Why look at Estriol instead of standard Estradiol?​​

Modern MHT formulations rely on estradiol, which is a potent activator of Estrogen Receptor alpha (ERα) - the receptor responsible for tissue proliferation in the breast and endometrium. Estriol, on the other hand, is a weaker estrogen prevalent during pregnancy that binds primarily to estrogen receptor beta (ERβ). Because ERβ is highly concentrated in the areas of the brain involved in verbal memory and executive function, the hypothesis is that estriol could offer targeted neuroprotection without the same peripheral proliferative risks of standard estradiol.​ Taking this further, in the clinical phase of the study, a small pilot cohort of 20 postmenopausal women took PearlPAK for 12 months. The packs contained estriol dosed at 2 mg, 4 mg, or 8 mg, and were paired with micronized progesterone (100 mg, 200 mg, or none for women without a uterus). They filled out a subjective survey at month 12, and the women reported statistically significant improvements in processing speed, working memory, concentration, and overall "brain fog.”​​

The Mechanism

​During the menopausal transition, the brain loses its primary signaling for glucose transport. Astrocytes (the cells responsible for supporting neurons) become less capable of metabolizing glucose. To compensate for this "energy crisis," astrocytes upregulate a protein called ENO1. Unfortunately, this triggers a cascade of neuroinflammation and synaptic pruning, the exact biological drivers of "brain fog." In animal models, the UCLA researchers found that estrogen-deficient mice exhibited clear cognitive and spatial memory deficits. However, when treated with estriol, cognition was restored. Mechanistically, estriol binds to ERβ in the brain, which reduces the expression of ENO1, resolves the cellular "low energy" state, and attenuates neuroinflammation.​​

The Clinical Pilot​

Taking this from mice to humans, the researchers conducted a small pilot cohort of 20 postmenopausal women who took PearlPAK for 12 months. The packs contained varying doses of estriol (2 mg, 4 mg, or 8 mg) paired with micronized progesterone. At month 12, the women reported statistically significant improvements on subjective surveys measuring processing speed, working memory, concentration, and overall "brain fog."​​

Clinical Reality & Limitations​

That said, there are several significant methodological limitations to this study, in addition to the very small sample size:

• No Head-to-Head: The study did not compare estriol's efficacy against our current gold standard (transdermal estradiol).
• Missing PK and Safety Data: There is a lack of clarity on the pharmacokinetics of various estriol administration routes, and no safety data to suggest estriol is safe for women who are otherwise contraindicated for standard estradiol therapy.
• Conflict of Interest: Both the patented hormone formulation (PearlPAK) and the subjective assessment tool were developed by the study’s senior author.

Conclusion

Whether you are navigating a patient's request for off-label testosterone or evaluating a midlife woman experiencing brain fog, modern menopause care is inherently complex. While large-scale RCTs are vital for establishing baseline safety, they ultimately report on population averages. In practice, individual pharmacokinetics, treatment response, receptor sensitivities, and symptom burdens vary wildly, reminding us that we must always treat the patient in front of us. Navigating this requires us to constantly balance between two extremes: the hype of social media trends on one side, and outdated, fear-based dogma on the other.​

We hope this month’s breakdown equips you with the nuanced data you need to prescribe with evidence-based confidence while listening closely to the individual needs of your patients.​

And if you are interested in trying our AI co-pilot hormone assistant tool to help you do so, access your 14-day free trial here: https://www.damaassist.com/chat​

Until next month!
The Dama Health team.