Doing It Right: What Good Testosterone Therapy in Women Actually Looks Like

Compounded Preparations Done Properly

In the absence of an approved product, thoughtfully prescribed compounded testosterone remains a reasonable option — when it is done with rigor. That means:

• Comprehensive baseline testing before initiation: total testosterone, free testosterone by LC-MS/MS with equilibrium dialysis where available, SHBG, and a full sex hormone panel including estradiol, progesterone, and DHEA-S
• Dosing formulated at female-physiologic concentrations by a compounding pharmacy with validated manufacturing practices — not a fraction of a men’s commercial product
• Regular follow-up monitoring of levels to confirm the patient is achieving physiologic range without accumulation or supraphysiologic drift
• Symptom correlation as the primary clinical target: resolution of androgen insufficiency symptoms at the lowest effective dose, not achievement of an arbitrary number on a lab report
• Urine hormone metabolite testing (such as the DUTCH test) to assess how testosterone is being processed, which pathways are active, and whether metabolites are accumulating in directions that warrant attention

Pellet Therapy: The Promise and the Pitfalls

Subcutaneous testosterone pellet implantation offers an appealing premise: consistent, steady-state hormone delivery over several months without the compliance burden of daily application. For some patients, this is genuinely valuable.

A limitation is dose inflexibility. Once a pellet is implanted, the dose cannot be adjusted downward. If levels overshoot — which can occur with imprecise initial dosing or individual variation in pellet absorption — the patient carries supraphysiologic testosterone until the pellet is exhausted, which may take three to six months.

Pellet therapy done responsibly requires conservative initial dosing, pre-insertion laboratory evaluation, follow-up levels at four to six weeks post-insertion, and a provider who has developed genuine expertise in female-specific dosing. It is not appropriate for every patient, and the irreversibility of an implanted dose demands careful selection and informed consent.

Understanding Testosterone Metabolism: It Is Not Just About the Level

Testosterone does not act in isolation. How the body metabolizes it shapes both the therapeutic response and the side effect profile. There are two primary downstream conversion pathways:

• Aromatization to estradiol — via the aromatase enzyme, particularly in adipose tissue. In most women, a small degree of aromatization is physiologically normal and contributes to estrogen balance. At appropriate physiologic doses of testosterone, this conversion is generally not a clinical concern. Monitoring estradiol levels as part of routine follow-up is sufficient to identify the uncommon situation where conversion is excessive.
• Conversion to dihydrotestosterone (DHT) — via 5-alpha reductase. DHT is a more potent androgen and is relevant to androgenic side effects such as acne and hair thinning.

SHBG must also be assessed as part of any testosterone evaluation. High SHBG binds testosterone and reduces bioavailability, meaning a woman with a “normal” total testosterone and elevated SHBG may have very little free, active hormone. Low SHBG, conversely, may allow greater free testosterone activity than the total level would suggest.

Two women on identical doses of testosterone can have very different clinical experiences depending on their individual metabolic enzyme activity. This is why the approach must be personalized — not protocol-driven.

A New Drug on the Horizon — But Not Without Questions: AVA-291 (d3-Testosterone)

What It Is and Why It Matters

AVA-291, developed by Aviva Bio, is an investigational deuterium-substituted isotopologue of testosterone. In plain terms: it is structurally identical to endogenous testosterone, but select hydrogen atoms have been replaced with deuterium — a naturally occurring, stable, non-radioactive heavy isotope of hydrogen with an atomic mass of 2 rather than 1.

The rationale for this substitution is specific and scientifically grounded. Deuterium-substituted bonds are more resistant to enzymatic cleavage than normal carbon-hydrogen bonds, due to the kinetic isotope effect. By placing deuterium at positions targeted by the aromatase enzyme, AVA-291 is engineered to resist aromatization — the conversion of testosterone to estradiol.

Aviva Bio frames aromatization as the primary safety concern justifying this structural modification, citing the theoretical link between local estrogen production in breast tissue and estrogen-receptor-positive (ER+) breast cancer risk. Preclinical data suggest AVA-291 stimulates ER+ breast cancer cell proliferation approximately 1,000-fold less than standard testosterone, with findings scheduled for presentation at the American Association for Cancer Research Annual Meeting in April 2026.

That premise deserves scrutiny. The FDA recently removed the black-box warning on estrogen therapy that had cast a long shadow over hormone replacement for more than two decades — a warning rooted in the misinterpretation of the Women’s Health Initiative data. That removal reflects a growing scientific consensus that estrogen, at physiologic doses, is not the carcinogenic agent it was once portrayed to be in healthy women without a personal history of hormone-sensitive cancer. If the foundational fear driving the aromatization concern has been substantially revised by the very regulatory body tasked with evaluating it, then the urgency of engineering around aromatization in the general female population requires re-examination.

For the small subset of women with a personal history of estrogen-receptor-positive breast cancer, the clinical picture is more nuanced — and there is meaningful work in this space. Dr. Rebecca Glaser’s research on subcutaneous testosterone pellet therapy using anastrozole co-pellets to locally block aromatization has demonstrated both safety and benefit in this population, providing a targeted solution for women who have the most legitimate reason to limit estradiol conversion. (13) That is a real solution to a real problem in a specific, identifiable subgroup. It is not, however, a justification for altering the molecular structure of testosterone for all women.

For the vast majority of women without a history of hormone-sensitive cancer, a small percentage of testosterone converting to estradiol is not a pathological event — it is physiology. Testosterone has always aromatized in women. The body has co-evolved with that process. Monitoring estradiol levels during therapy, adjusting dose appropriately, and selecting a route of administration that minimizes supraphysiologic peaks are sufficient, evidence-aligned strategies for managing aromatization in the general population. Deuterium substitution is not required.

In January 2026, Aviva Bio received positive formal guidance from the FDA via a Type B meeting, clarifying the regulatory development pathway for a women’s testosterone therapy. A Phase 1 clinical trial was announced for early 2026. As of this writing, no interim human data have been publicly reported.

This represents the first serious regulatory pathway toward an FDA-approved testosterone product specifically designed for women. That is genuinely significant, and it deserves acknowledgment. Women have waited a very long time for this.

Why Scientific Caution Is Also Warranted: The Deuterium Question

With that acknowledgment made, I want to raise a question that I believe deserves serious consideration before AVA-291 — or any deuterium-labeled steroid — is adopted as a standard of care for millions of women.

Deuterium is not inherently dangerous. It is present in biological systems at trace concentrations — approximately 0.015% of hydrogen atoms in natural water. At physiological ambient concentrations, it poses no known harm. Deuterium-substituted pharmaceuticals are not new: deutetrabenazine (Austedo), FDA-approved for Huntington’s disease chorea, uses the same strategy and has demonstrated an acceptable safety profile with reduced side effects compared to its non-deuterated parent compound.

However, the specific question of chronic systemic exposure to a deuterium-labeled steroid hormone — one that circulates throughout the body, enters the brain, bone, breast, and muscle — over months to years has not been studied in human trials. That is not the same as saying it is unsafe. It is saying we do not yet know.

Research by Stephanie Seneff and colleagues at MIT raises a theoretical concern worth noting. In a 2025 review published in FASEB BioAdvances, Seneff, Nigh, and Kyriakopoulos proposed that deuterium, at elevated concentrations in mitochondria, can interfere with the rotary mechanism of ATP synthase — the molecular motor responsible for generating ATP — by virtue of its greater mass and the resulting kinetic isotope effect on hydrogen-dependent reactions. (8) The proposed consequence is reduced ATP production and increased output of reactive oxygen species (ROS), contributing to mitochondrial dysfunction.

It is important to be precise about what this research does and does not claim. Mainstream scientific consensus holds that deuterium-substituted drugs at therapeutic doses do not produce systemic deuterium accumulation sufficient to disrupt mitochondrial function. The kinetic isotope effect in a deuterated pharmaceutical is exploited at the level of specific metabolic bonds in the drug molecule — not distributed throughout cellular water. Seneff’s broader hypotheses about deuterium, chronic disease, and glyphosate remain speculative and are not established consensus science.

That said, the question is not unreasonable to ask: when a deuterium-labeled steroid is administered chronically to women — a population that may use testosterone therapy for years to decades — what is the long-term fate of that deuterium label? Does it accumulate in tissues? Does it enter pathways relevant to mitochondrial hydrogen cycling? Does it behave differently than deuterium in a small-molecule neurological drug with a very different tissue distribution profile?

These questions have not been answered by existing preclinical data, and they are appropriate questions to ask before widespread clinical adoption.

The Chronic Illness Context: “Won’t Kill You” Should NOT be the Standard

Here is the broader concern that I cannot set aside, and it goes beyond the pharmacology of AVA-291 specifically. We are not prescribing into a healthy population. We are prescribing into a population in which chronic illness has become the statistical norm.

According to the CDC, approximately 60% of American adults have at least one chronic disease, and 40% have two or more. Conditions once considered diseases of aging — metabolic dysfunction, autoimmunity, cognitive decline, persistent fatigue, inflammatory disorders — are now presenting in younger and younger patients. Chronic fatigue, in particular, has become so pervasive that many people have quietly reclassified it as a normal feature of modern life rather than a symptom that warrants investigation. It is not normal. But it is increasingly common.

This matters to the deuterium discussion in a specific way. The preclinical safety argument for AVA-291 is built, in part, on the premise that therapeutic doses of a deuterium-substituted compound will not produce systemic deuterium accumulation sufficient to cause harm. That argument is derived from studies of deuterium toxicity in otherwise healthy biological systems. But many of the women who will be prescribed this medication — if it is approved — are not operating in otherwise healthy biological systems. They are women with mitochondrial dysfunction already expressed as fatigue. Women with pre-existing inflammatory burden. Women with impaired detoxification capacity, gut dysbiosis, or years of accumulated environmental toxic load from pesticides, plasticizers, heavy metals, and other endocrine-disrupting compounds.

The threshold at which “won’t cause harm” is established in a healthy, well-functioning system may not be the same threshold that applies to a woman already carrying a substantial allostatic load. If Seneff’s proposed mechanism — that deuterium interferes with ATP synthase efficiency and increases reactive oxygen species output — has any validity at physiologically relevant concentrations, then the women most likely to be harmed are precisely those who are already the most metabolically compromised. They are also, not coincidentally, often the women most likely to be seeking testosterone therapy in the first place.

This connects to a principle I hold across all of clinical medicine: the goal of therapeutic intervention should not be merely to avoid acute harm. It should be to restore and support the body’s innate capacity to function. Every substance we introduce — every medication, every supplement, every intervention — is either contributing to that goal or working against it. The standard of “it won’t kill you” is not a standard at all. It is the lowest possible bar, and chronically ill patients deserve better than the lowest bar.

We are already living in a sea of toxicants. Glyphosate residues are detectable in human urine, breast milk, and cerebrospinal fluid. Phthalates and bisphenols are measurable in the vast majority of Americans tested. Per- and polyfluoroalkyl substances (PFAS) have been found in human blood at detectable concentrations across all age groups. Heavy metals accumulate in bone and brain tissue over decades. The body is not infinitely resilient in the face of this ongoing exposure. Its buffering capacity — its ability to manage, metabolize, and eliminate what does not belong — is finite, and for many patients, it is already strained.

Against that backdrop, the question I am compelled to ask is not “is this dose of deuterium acutely toxic?” The question is: why would we deliberately engineer a foreign isotope into a hormone medication when a chemically identical, isotopically natural alternative — bioidentical testosterone — already exists and can be compounded at female-physiologic doses? For the majority of women, aromatization at physiologic testosterone doses is not a problem to be solved — it is a normal biochemical process. Where aromatization does warrant attention, such as in women with a history of estrogen-receptor-positive breast cancer, targeted solutions already exist. The broad aromatization concern does not justify a structural modification to the hormone molecule for the general female population.

The chronic illness epidemic mushrooming across our society did not arise from a single cause. It arose from the accumulation of many small insults — each one, in isolation, deemed acceptable by the standards of the day. We should be asking whether each new therapeutic addition reduces that burden or adds to it. That is not obstructionism. That is the practice of medicine with a long view.

The Core Tension

We may be at risk of replacing one inadequately studied approach — off-label male formulations — with a novel molecular entity whose long-term isotope-related biology has not been characterized in human studies. The history of women’s hormone therapy is already marked by treatments that were adopted with enthusiasm before long-term data were available, with consequences that took decades to understand.

Supporting the development of AVA-291 and asking rigorous questions about it are not mutually exclusive positions. They are both part of practicing evidence-based medicine on behalf of women. The goal is not to obstruct progress. The goal is to ensure that when an FDA-approved testosterone product for women finally arrives, it is one whose long-term safety we have genuinely earned the right to assert.