The FDA just removed a 23-year warning 🧬

LONGEVITY LATEST

The Evidence-Based Edge on Living Longer and Better

Issue 11  ·  20 May 2026

Two hormone files that shaped a generation of clinical caution have been quietly rewritten in the last six months — and the wellness clinics are about to misread both.

In November, the FDA pulled the black-box warning off menopausal hormone therapy. Five months earlier, the largest cardiovascular safety trial ever run on testosterone — 5,246 men, three years of follow-up, commissioned at the FDA's own request — landed with no signal on the composite outcome of cardiovascular death, heart attack, and stroke.

This issue grades what is now defensible, names the £400-a-month clinics about to ride the rebound, and tells you which form of which hormone the trial data actually supports — not what the press release implies.

In this issue:

🔬  Top 3: TRT for symptomatic hypogonadism, transdermal HRT within the 10-year window, testosterone for HSDD in women

⭐  Spotlight: Transdermal estradiol — what the post-WHI re-analysis actually shows

🚨  Hype Check: Testosterone pellet clinics — BioTE, Defy, and the £400 problem

🍫  Superfood: Pomegranate (the endothelial case)

📖  Deep Dive: What the WHI got wrong — and what the re-analysis won't fix

🌡  Biohacking Corner: Earning the optimised number before you buy it

1. Testosterone Replacement Therapy (Men)  — Evidence Grade: B+

What it is. Exogenous testosterone — gel, patch, or intramuscular injection — for men with symptomatic hypogonadism and two morning total testosterone readings below ~10.4 nmol/L. Clinically available since the 1950s. Carried a black-box CV warning the FDA never quite found the courage to either justify or remove.

Human evidence. TRAVERSE (Lincoff et al., NEJM 2023) was commissioned by the FDA to settle a fifteen-year argument. 5,246 men aged 45–80 with established or high-risk cardiovascular disease, randomised to transdermal testosterone gel or placebo, 32.9 months follow-up. The primary endpoint came in flat. The trial designed to confirm the warning quietly retired it.

Picture isn't spotless. The same cohort showed a small but real increase in non-fatal arrhythmias, venous thromboembolism, and — unexpectedly — fractures (Snyder, NEJM 2024). The European Expert Panel on Testosterone Research (Andrology 2026) read TRAVERSE as definitively neutralising the CV concern in correctly selected patients.

Cautions. TRT is for biochemical hypogonadism, not for a stressful job and a low-normal number. Polycythaemia above haematocrit 54% needs dose reduction or therapeutic phlebotomy. Untreated severe sleep apnoea, untreated prostate cancer, and recent MI remain contraindications. PSA and haematocrit at 3, 6, and 12 months. The fracture signal is the part nobody fully explains yet — flag it and watch the follow-ups.

Takeaway. The cardiovascular case against TRT was never as strong as the warning suggested. TRAVERSE has now buried it. Evidence Grade B+. The number to beat is symptoms, not someone else's lab range.

Personal note: I run mine in the 18–24 nmol/L band — mid-range, not "optimised" — on transdermal gel. The clinic that offered to get me to 35 was politely declined.

2. Transdermal Estradiol (Within 10 Years of Menopause)  — Evidence Grade: A

What it is. Bioidentical estradiol, patch or gel, paired with progesterone in women with a uterus. Bypasses the liver's first-pass — which is the part that matters. Available cheap on the NHS and across European pharmacies.

Human evidence. Two threads. First, the timing-hypothesis re-analyses of WHI (Manson et al., JAMA 2017, n=27,347, 18-year follow-up): in women starting HRT within 10 years of menopause, the harms driving the 2002 warning largely disappeared, and all-cause mortality trended favourably. The original signal came mostly from women a decade or more past menopause on oral conjugated equine oestrogen plus medroxyprogesterone — not how anyone serious prescribes HRT now.

Second, the route question. A 2024 route-stratified secondary analysis of WHI (Boardman, AJPC 2024) found oral arms reproduced the VTE signal; transdermal arms showed no clear increase in any CV outcome and a borderline reduction in MI and composite CVD. The 2022 Vinogradova systematic review (51 studies) flagged VTE as the clearest difference — higher with oral, near-baseline with transdermal.

On 10 November 2025, the FDA initiated removal of the cardiovascular, breast-cancer, and dementia warnings from systemic HRT products. The agency's framing — "50% reductions in heart attack risk" — is more aggressive than the mortality data supports. The direction is correct, and twenty-three years overdue.

Cautions. Active or recent breast cancer remains an absolute contraindication. Migraine with aura, active liver disease, undiagnosed vaginal bleeding, and prior VTE need a menopause specialist — not the practice nurse, not a TikTok influencer. The endometrial-cancer warning on estrogen-alone products has not been removed, and shouldn't have been.

Takeaway. For symptomatic women within 10 years of menopause, transdermal estradiol plus progesterone is the safest, best-evidenced systemic formulation we have. Evidence Grade A. Timing plus route is doing nearly all the work the FDA reversal claims credit for.

3. Testosterone Therapy in Women (for HSDD)  — Evidence Grade: C+

What it is. Low-dose transdermal testosterone — roughly one-tenth the male dose — for postmenopausal women with hypoactive sexual desire disorder where other causes have been excluded. No FDA-approved female formulation exists in any country. Prescribing is off-label.

Human evidence. The cleanest read is Islam, Davis et al. (Lancet Diabetes & Endocrinol 2019, 36 trials, 8,480 women). Testosterone at physiological doses improved satisfying sexual events, desire, arousal, orgasm, and self-image, with reductions in sex-related distress. Roughly one additional satisfying sexual event per month — modest, but real and consistent. The Global Consensus Position Statement that followed (Davis, JCEM 2019, co-signed by 11 societies) endorsed testosterone for postmenopausal HSDD as the only evidence-based indication.

Outside HSDD, the evidence falls off a cliff. The "low T causes brain fog in women" framing driving the optimisation-clinic market has essentially no controlled trial support.

Cautions. Supraphysiological doses cause acne, hirsutism, voice deepening, and clitoromegaly that doesn't fully reverse — which is why physiological female ranges matter (total T roughly 0.5–2.5 nmol/L). Anything higher is recreational endocrinology, not medicine. The "how" of delivery is its own question, and the answer is in this issue's Hype Check.

Takeaway. For postmenopausal HSDD with obvious causes excluded, transdermal testosterone at physiological female doses is reasonably supported. Evidence Grade C+. For energy, mood, cognition, or general optimisation, it is not.

Transdermal estradiol has the strangest evidence arc of any intervention this newsletter has graded. A trial that scared the category off the shelf in eighteen months, then a twenty-year quiet rehabilitation nobody had the appetite to convert into a headline — until November.

The WHI used oral conjugated equine oestrogen plus medroxyprogesterone in women whose median age was 63 — a decade past the window where the timing hypothesis predicts benefit. It found increased breast cancer, stroke, VTE, and coronary events. The black box went on every estrogen-containing product, regardless of route or age. The EMA never followed.

The trial that scared HRT off the shelf was run in women a decade past the window where the data say it works.

What the re-analyses have established since 2007 is consistent: harm was concentrated in the older, oral, conjugated-equine subgroup. Younger women, transdermal route, lower doses — the harm largely disappears, the VTE signal collapses, and the cardiovascular numbers flatten or trend favourable.

Pros

✓  Vasomotor symptoms reduce by ~75% in the first 12 weeks.

✓  Bone density preserved; fracture risk down 30–40% in the WHI fracture analyses.

✓  Transdermal route avoids the first-pass hepatic effect — materially lower VTE and stroke risk than oral oestrogen.

Cons

⚠  Active or recent breast cancer remains an absolute contraindication. The "every woman should be on HRT" framing overshoots.

⚠  The FDA's "50% heart attack reduction" line is more aggressive than the 18-year mortality data supports. Manson 2017 found no significant mortality benefit overall.

⚠  Endometrial-cancer warning on estrogen-alone products in women with a uterus remains, correctly.

Bottom line: ✅ Evidence supports use in correctly selected women — within 10 years of menopause, transdermal route, lowest effective dose, with progesterone if the uterus is intact. The reversal is overdue. The PR around it is one click ahead of the trial data.

The Hype. BioTE (UK partner clinics, £350–£500 per insertion, three to four insertions a year), Defy Medical ($250–$400 per round plus consults), and a growing network of "hormone optimisation" boutiques implant compounded testosterone pellets — rice-grain pucks of pressed hormone — under the skin every three to four months. Marketing claims now span energy, libido, cognition, body composition, mood, and "biological age reversal". Many clinics offer the same protocol to women.

The Evidence. No RCT of compounded hormone pellets has ever been published. Then in 2018 the FDA inspected BioTE Medical and found something worth sitting with.

4,202 adverse events. Never reported. Over five years.

The FDA itself described those events as suggestive of endometrial cancer, prostate cancer, strokes, heart attacks, deep vein thrombosis, cellulitis, and pellet extrusion. ACOG's 2023 clinical consensus went further and explicitly recommended against pellets for testosterone delivery in women — because if the dose is wrong, you can't take a pellet out.

The pharmacokinetics tell the rest. A pellet releases hormone in an uncontrollable curve — peaking high in the first month, drifting low by month four. Supraphysiological levels above 35 nmol/L in men and above 5 nmol/L in women are routine.

Why It's Misleading. The "pellets are bioidentical and therefore safer" framing conflates two unrelated claims. The molecule is identical to endogenous testosterone — true. The pellet formulation is not FDA-approved, often not produced under outsourcing-facility controls, and impossible to titrate once implanted. Convenience buries the problem.

Our Verdict: ❌ Skip it. Clean alternatives exist and are cheap. For men, transdermal gel through an NHS or licensed private endocrinologist runs £30–£80 a month, with titratable serum levels and a real prescriber. For women with HSDD, off-label transdermal at one-tenth the male dose under a menopause-trained gynaecologist gives a controlled, reversible trial. The £400 per implantation buys you the one form of delivery the dose can never be corrected for.

The same nitric-oxide pathway transdermal estradiol gently nudges, available in a fruit. Pomegranate is unusually rich in punicalagins and ellagic acid — polyphenols that improve endothelial function in measured trials, not just marketing decks.

A 2017 meta-analysis (Sahebkar, Pharmacological Research, 8 RCTs) found pomegranate juice cut systolic BP by 4.96 mmHg and diastolic by 2.01 mmHg — on a par with a low-dose ACE inhibitor in some subgroups. A 2024 RCT (n=83 postmenopausal women, 8 weeks) saw improved flow-mediated dilation and lower hs-CRP at 240 ml/day. Aim for 100–250 ml of pure juice (not "drink") or a handful of arils a day, with meals to blunt the sugar curve. A 100g pack of fresh arils runs about £2.50.

The FDA didn't reverse the WHI. It reversed the over-reading of the WHI.

Buried in the Manson 2017 18-year follow-up is a fact nobody quoting the FDA's "50% heart attack reduction" line is mentioning: in the overall WHI cohort, all-cause mortality on hormone therapy was statistically indistinguishable from placebo. The directional benefit in the 50–59 subgroup is real — but it doesn't carry the magnitude the November press release claimed.

This week's companion article walks the file the way an analyst would: what WHI found, what it didn't test, where the timing hypothesis comes from, why the route question matters more than the FDA admits, and what the re-analysis still cannot answer.

👉 Read: What the WHI Got Wrong — And What the Re-Analysis Won't Fix
1,400 words  ·  7-minute read

A non-trivial fraction of men asking about TRT and women asking about testosterone are running endocrine systems lifestyle alone would meaningfully recover. Before prescriptions:

1.  Sleep first. Total testosterone drops measurably after one week of restricted sleep — Leproult & Van Cauter (JAMA 2011) showed a 10–15% reduction at five hours a night. Untreated obstructive sleep apnoea is the single most common cause of avoidable hypogonadism in TRT consultations.

2.  Body composition beats supplements. Visceral fat aromatises testosterone to oestradiol. Losing 5–10% body weight raises total T by 2–3 nmol/L on average. A man at 28% body fat asking about TRT often doesn't need TRT yet.

3.  Lift heavy, twice a week. Compound lifts, real load. The chronic effect on insulin sensitivity, body composition, and SHBG is where the benefit lives — not 90-minute accessory routines.

4.  Run the labs first. Total and free testosterone (morning, fasted, two readings a week apart), SHBG, LH, FSH, ferritin, vitamin D, thyroid panel, HbA1c. Half of low-T patients have an obvious upstream cause when you check.

Caveat: this is for the borderline-low cohort, not symptomatic hypogonadism with twice-confirmed sub-10.4 nmol/L numbers. There, the trials say treat.

Personal note: I went through the labs-first stage twice before agreeing to TRT. Round one: 11.2 nmol/L, untreated sleep apnoea, eighteen kilos of visceral fat. Round two, a year later: 15.1 nmol/L. Still symptomatic, but the easy gains were genuinely spent. That's the number the clinic conversation should start from.

Last week's sauna poll drew nearly four hundred votes. Just under a fifth of you run the Finnish-cohort dose (4+ a week), about a third are at 1–3 sessions, another quarter use a sauna occasionally when travelling, and the remaining 22% have no access. Editorial take: access is the real story. Most British gyms have a sauna; not all keep it at the temperature the trial data was earned at.

One ask: if you read this and thought of a specific person — a partner, a sibling, a friend on a pellet protocol — forward it. The TikTok version of this story is winning. The data-first version needs the help.

Issue 12 turns to peptides — BPC-157, the GLP-1 family beyond Ozempic, and a Hype Check on the "research peptide" reseller market nearly a fifth of you have apparently been buying from.

Stay curious and stay healthy!

— Christian Thomsen, Editor

Longevity Latest is published weekly by FrontWave Media Ltd. The content is for educational purposes and does not constitute medical advice. Hormone therapy in particular requires individualised assessment by a qualified prescriber. Consult your physician before starting, stopping, or changing any prescription medication, especially if you are pregnant, nursing, managing a cardiovascular or thrombotic condition, or have a personal or family history of hormone-sensitive cancer.