Against The Clock: articles and episodes

GLP-1 surprise pregnancies, female hormones, and sex after 40 for both of you

2026-11-11T00:00:00Z

A full hour on sex and hormones, and we barely got through the list.

What we covered

GLP-1s and unexpected pregnancy. A warning from the OB/GYN chair: women who've been overweight often don't ovulate regularly because of estrogen made in fat tissue. Lose the fat, get insulin sensitive, and ovulation comes back. We're seeing pregnancies in women who thought they couldn't conceive. If you're prescribing GLP-1s to a woman of childbearing age, have the birth control conversation, and if she wants to conceive, start the prenatal vitamin before she knows she's pregnant, because the neural tube closes before a missed period. Same rule as testosterone in men: it is not contraception.

Nobody asks women about sex. About one in four women report a desire or arousal problem, and we think the real number is higher, because "are you sexually active?" is a useless question and women don't bring it up with male doctors. Better openers: "how's your libido?" and, for anyone, "how is it on vacation, with no kids?" If the answer is "much better," the problem isn't a hormone.

How female hormones decline. The three-minute version: progesterone falls away from estrogen in the 40s, women get put on an SSRI for it, and the SSRI kills libido. Testosterone matters in women too and is usually ignored. The 2002 Women's Health Initiative study scared a generation of doctors off hormone therapy; the data has since been reread. One tell for ovarian decline: a woman who is intensely emotional in the days before her period.

Forms of hormone therapy. We all agree compliance beats everything: whatever form the patient will use consistently. Where we differ is on the details.

Estradiol: patches for consistency, topical for lower clot risk than oral, or intramuscular injection for the steadiest levels. Patches fall off; creams absorb unevenly and transfer to kids and pets.
Progesterone: oral micronized, nightly, not cyclically. If a woman can't tolerate a full dose and has to go lower, she needs periodic pelvic ultrasound to check the endometrium. For breakthrough bleeding on injectable estradiol, a low-dose levonorgestrel IUD stabilizes the lining locally with almost no systemic effect. This one changed one of our practices on air.
Testosterone in women: two of us have moved from creams to weekly or twice-weekly low-dose injections of compounded testosterone. Women feel the difference even when blood levels look the same on cream. Why: skin absorption converts more to DHT (hair loss, acne), and the lymphatic route is unreliable.

Labs. Estradiol has to be the high-sensitivity LC/MS assay or the number is useless. On a cycling woman, draw on day 19 to 21. In perimenopause, draw the morning after a bad night of hot flashes, when FSH and LH are most likely to show it. What FSH, LH, E1, E2 and E3 are. On estriol face creams: holy water.

Perimenopause. Two descriptions from the table: an old truck that runs some days and not others, and ovaries with early dementia. Labs are a snapshot; menopause is defined by a year without periods, not by a number. Educated patients can titrate their own estrogen by symptoms, with progesterone every night.

How to bring it up with your doctor. Not at the 15-minute annual. Book a separate visit and say it's about your sex life. Searching for a BHRT physician is one route, with a caveat: we see 25-year-olds on testosterone and premenopausal women on high-dose estrogen pellets, so credentials and physiology matter. Expect to pay out of pocket for the time.

Men. The ones whose hormones and PDE5 inhibitors are dialed in but "it still isn't working" usually have a stress problem no drug fixes. Sleep apnea is the most common thing under a dead sex drive, and testosterone makes apnea worse. Arterial plaque shows up in erections before it shows up as heart disease; what shockwave therapy does and why getting a morning erection back fixes the psychological half. The tech and founder patients who are on every peptide and still not sleeping.

Receptor fatigue and pellets. The package-in-the-foyer analogy: a steady hormone level stops working as receptors down-regulate. Drop the testosterone dose for a few weeks, then back up, and libido returns. Only one of us uses pellets, and only in women: men need 9 to 15 pellets through three tracks, with bruising and scarring, and once they're in you can't lower the dose. Bodybuilders as the natural experiment: more isn't better, more is more side effects. Use a major lab like Quest or Labcorp; most independent labs' assays aren't trustworthy.

Timestamps

00:00 Intro
01:19 GLP-1s and surprise pregnancies
06:25 The question nobody asks women
15:21 Female hormone decline and the WHI study
18:35 Patches, creams, pills, injections: what each of us uses
28:33 Progesterone dosing, endometrial protection, and the IUD trick
35:49 Perimenopause: when to draw labs
40:30 FSH, LH, and the three estrogens
43:16 How to bring this up with your doctor
46:41 Men: libido, ED, and stress
48:40 Sleep apnea
50:30 Blood flow, PDE5 inhibitors, shockwave therapy
53:32 Receptor fatigue and the case against pellets
58:43 Injectable testosterone for women
1:00:57 Not medical advice, and why the first visit takes two hours

Sources

Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288(3):321-333.
Manson JE, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

GLP-1s, Bryan Johnson's routine, and whether NAD is worth your money

2026-11-04T00:00:00Z

The first episode. The four of us introduce ourselves and get into the three questions patients ask most right now.

What we covered

GLP-1s (semaglutide, tirzepatide, retatrutide). These drugs aren't new; Byetta and Bydureon were out 20 years ago with side effects patients couldn't tolerate. The change came when the once-weekly versions arrived and the drugs started being given to people who weren't diabetic. Between us we have several years of patient data: consistent fat loss, improving liver numbers, and lean mass holding up when patients lift and hit their protein. We don't all use them the same way. One approach is to add them after a year of lifestyle work hasn't moved the needle, with the behavior change pushed alongside. Another was to hold out for years, then watch the results in insulin-resistant patients who were already exercising and eating well. The cautious view at the table: blunted mood in some patients, slowed gut motility, and no good answer yet to how long people stay on them, so use a low dose as an assist and plan the exit.

Insulin, not weight, is the target. Why a fasting insulin that's still high 12 hours after eating makes fat loss close to impossible, and why the GLP-1s are an insulin treatment first. We disagreed on what happens to fasting insulin on the drugs: some of us see it fall as visceral fat falls; others see it run a little higher for the first year or two, probably from slowed stomach emptying. The open question: what does that mean for an insulin-sensitive person who takes it for a quick ten pounds?

Hemoglobin A1c is a calculation, not a measurement. It assumes red cells live 90 days. Real red cells live 66 to 120. Trends and a continuous glucose monitor tell you more than one number.

Gray-market retatrutide. Patients are buying it from research chemical suppliers. All four of us say don't: you don't know what's in the vial, the sterility, or the other chemicals. If you can't get most of the way there on semaglutide or tirzepatide from a real pharmacy, the problem isn't which drug you're on.

Bryan Johnson, Huberman, Attia, and the protocol problem. We read out Bryan Johnson's daily schedule. Our point: most of the loudest voices online don't manage patients, mouse studies don't translate, and an N of 1 with a billion dollars isn't a plan for a busy parent. Three tiers for any patient: fix what's broken, optimize what isn't, then extra credit like red light and hyperbaric oxygen if you want it. And the study that said diabetics lose three years: read it the other way too.

Extreme diets. Keto, carnivore, and the honeymoon phase every restrictive diet has. What happened to Robb Wolf after six months of it. One rule we all liked: eat food you cooked at home.

NAD. Split table. One of us stopped recommending it over the cancer question and prefers glutathione. One likes the concept, doesn't trust injected NAD to get where it needs to go, and also prefers glutathione. One was early on IV NAD and still thinks an occasional IV "top-off" makes more sense than daily pills, but hasn't needed one in a couple of years. Nobody has a lab test to tell who's deficient. What the infusion feels like, and the niacin-style flush from the injections.

Glutathione. Oral only works as S-acetyl glutathione; otherwise it's a shot, an IV, or sublingual. Three of the four of us take it.

The one thing. Our answers: there isn't one, it's the fundamentals; walk; nutrition first, then exercise; and read Atomic Habits so you learn how to build the habit, whatever the habit is.

Timestamps

00:00 Who we are
05:22 GLP-1s: four doctors, four takes
17:18 Why insulin is the real target
23:00 A1c is a calculation; use trends and a CGM
24:58 Gray-market retatrutide
27:50 Bryan Johnson's schedule and the influencer problem
33:03 Three tiers: broken, optimize, extra credit
36:48 Keto, carnivore, and the honeymoon phase
39:36 NAD: who takes it, who stopped
52:03 Glutathione and the pill burden
55:43 The one thing each of us would tell you

Mentioned

Atomic Habits by James Clear
The Miracle Morning by Hal Elrod
Bryan Johnson's Blueprint protocol
Robb Wolf and the paleo diet

A note on the disagreements

We didn't agree on fasting insulin on GLP-1s or on NAD, and we left it that way. That's the point of four doctors in a room.

GLP-1 medications beyond weight loss: how far do the benefits extend?

2026-11-04T00:00:00Z

GLP-1 receptor agonists began as diabetes drugs and became weight loss drugs. Since March 2024 the FDA has added approvals for cardiovascular risk reduction (semaglutide, March 2024), obstructive sleep apnea (tirzepatide, December 2024), chronic kidney disease in type 2 diabetes (semaglutide, January 2025), and MASH, the inflammatory form of fatty liver disease (semaglutide, August 2025) [1]. Trials are running in conditions further still from their origin. For each new indication, the question worth asking is how much of the benefit is explained by weight loss and blood sugar improvement, and how much is left over once those are accounted for.

Sorting the evidence that way produces three groups.

Mostly explained by weight loss

Sleep apnea. In the two SURMOUNT-OSA trials (469 adults with moderate to severe apnea and obesity, baseline apnea-hypopnea index about 50 events per hour), tirzepatide cut the index by 25 to 29 events per hour over 52 weeks, against 5 on placebo, while body weight fell 18 to 20 percent [2]. Weight loss by any method does something similar. In the Wisconsin Sleep Cohort, a 10 percent weight loss predicted a 26 percent fall in the index, and a 10 percent gain predicted a 32 percent rise [3]. The drug's effect on apnea is roughly what its weight loss would predict.

Fatty liver disease (MASH). In ESSENCE, 800 adults with MASH and moderate to advanced fibrosis received semaglutide 2.4 mg or placebo. At 72 weeks, steatohepatitis resolved without worsening fibrosis in 62.9 percent on semaglutide versus 34.3 percent on placebo, alongside weight loss of 10.5 percent versus 2.0 percent [4]. Weight loss on its own does much of this: in a 2015 lifestyle study of 293 patients with biopsy-proven NASH, 90 percent of those who lost 10 percent or more of their body weight had resolution of steatohepatitis [5]. Exploratory analyses of ESSENCE split the drug's liver effect roughly in half between weight-dependent and weight-independent parts, with the weight-independent share for MASH resolution estimated near 52 percent [6]. The authors flag that these mediation models rest on assumptions that cannot all be tested.

Heart failure with preserved ejection fraction. In STEP-HFpEF (529 patients with HFpEF and obesity), semaglutide improved the KCCQ symptom score by 7.8 points more than placebo and six-minute walk distance by 20.3 meters, with weight loss of 13.3 percent versus 2.6 percent [7]. A prespecified analysis found the gains scaled with weight lost: about 6.4 KCCQ points and 14.4 meters per 10 percent of body weight [8]. SUMMIT (731 patients) then tested tirzepatide against a hard endpoint and found a 38 percent lower rate of cardiovascular death or worsening heart failure (9.9 versus 15.3 percent, hazard ratio 0.62). The difference came from worsening heart failure events; cardiovascular deaths were few and did not differ [9]. Weight appears to be the main driver here, though the STEP-HFpEF investigators did not think it explained everything, and inflammation (CRP) fell as well.

Partly explained

Cardiovascular events. SELECT randomized 17,604 adults with established cardiovascular disease and overweight or obesity, but no diabetes, and found semaglutide cut major cardiovascular events by 20 percent over a mean follow-up of 39.8 months [10]. Two findings complicate a pure weight-loss story. The protection was similar across baseline HbA1c groups and regardless of how much HbA1c fell [11]. And weight loss at week 20 showed no relationship to later events, whereas reduction in waist circumference did; in the prespecified mediation analysis, waist reduction accounted for an estimated 33 percent of the benefit and weight loss for none [12]. A separate mediation analysis that modeled 12 risk factors together could explain about 31 percent of the effect in total [13]. The remaining share is unassigned. Inflammation and plaque biology are candidates; neither is proven.

Kidney disease. FLOW, the first dedicated kidney outcomes trial of a GLP-1 drug, enrolled 3,533 adults with type 2 diabetes and chronic kidney disease. Semaglutide cut the composite of kidney failure, sustained loss of kidney function, or kidney or cardiovascular death by 24 percent (hazard ratio 0.76) and slowed the yearly decline in filtration rate by 1.16 mL/min/1.73 m², with a weight difference of only about 4 kg between groups [14]. FLOW itself did not publish a mediation analysis. An exploratory analysis of two earlier semaglutide and liraglutide trials attributed about 25 percent of the kidney effect to HbA1c, with wide confidence intervals, and found no mediation by HbA1c in patients whose filtration rate was already below 60 [15].

Hard to explain by weight loss

Pressure inside the skull. Idiopathic intracranial hypertension is raised pressure around the brain, mostly in younger women with obesity, and it threatens vision. In a trial of 16 women with implanted telemetric pressure monitors (15 completed), exenatide lowered intracranial pressure by 5.7 cm of CSF at 2.5 hours after the first dose (p = 0.048) and by 6.4 cm at 24 hours; the 12-week reduction of 5.6 cm fell just short of conventional significance (p = 0.058) [16]. Weight cannot change on a 2.5-hour timescale. The proposed route is GLP-1 receptors in the choroid plexus, where the drug reduced cerebrospinal fluid secretion in rat studies [17]. One small trial is a signal, not a treatment; a phase 3 trial is the stated next step.

Alcohol use disorder. Four randomized trials have now tested GLP-1 drugs against drinking, with mixed results. A 2022 Danish trial of weekly exenatide in 127 treatment-seeking patients missed its primary endpoint of heavy drinking days, but found reduced drinking in the subgroup with obesity and, on brain imaging, quieter responses to alcohol cues in the ventral striatum [18]. A 2025 trial of low-dose semaglutide in 48 non-treatment-seeking adults over nine weeks reported fewer drinks per drinking day and lower craving; participants lost about 5 percent of body weight [19]. A 2026 trial of oral semaglutide in 50 adults over eight weeks missed its primary endpoint of laboratory-provoked craving but reported fewer heavy drinking days in weeks 5 to 8 [20]. The largest, SEMALCO, gave 108 treatment-seeking adults with obesity semaglutide 2.4 mg or placebo for 26 weeks on top of cognitive behavioral therapy; heavy drinking days fell 13.7 percentage points more on the drug [21]. The trials are small and short, and none was built to separate a reward effect from nausea and appetite suppression. That the clearest signals come from patients with obesity is a reason for caution about a weight-independent mechanism.

Limits of the evidence

The hard-endpoint results, in heart and kidney outcomes, come from trials of patients with established disease, diabetes, or obesity. Whether any of this extends to lean, metabolically healthy people taking these drugs for prevention has not been tested. Claims about Alzheimer's disease, cancer, or aging itself rest on observational data and trials still in progress.

Sources

U.S. Food and Drug Administration approvals: Wegovy (semaglutide) cardiovascular risk reduction, March 2024; Zepbound (tirzepatide) for obstructive sleep apnea, December 2024; Ozempic (semaglutide) for chronic kidney disease in type 2 diabetes, January 2025; Wegovy for noncirrhotic MASH with moderate to advanced fibrosis (accelerated approval), August 2025. Summarized in: BioSpace, "Wegovy cardiovascular approval furthers march into new indications" (2024); Pharmaphorum, "Ozempic is first GLP-1 drug FDA-approved for kidney disease" (2025); HCPLive, "FDA approves semaglutide (Wegovy) injection 2.4 mg for noncirrhotic MASH" (2025).
Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391:1193-1205. https://doi.org/10.1056/NEJMoa2404881
Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA. 2000;284(23):3015-3021. PMID 11122588.
Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis (ESSENCE). N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2413258
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367-378.e5. https://doi.org/10.1053/j.gastro.2015.04.005
Newsome PN, et al. Weight-dependent and -independent effects of semaglutide in participants with MASH: secondary analysis of the phase 3 ESSENCE trial. Abstracts presented at the European Congress on Obesity 2025 and AASLD The Liver Meeting 2025. Summary: EMJ Reviews, "Semaglutide improves MASH through weight-independent effects" (2025).
Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity (STEP-HFpEF). N Engl J Med. 2023;389(12):1069-1084. https://doi.org/10.1056/NEJMoa2306963
Butler J, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nat Med. 2023. https://doi.org/10.1038/s41591-023-02526-x
Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity (SUMMIT). N Engl J Med. 2025;392:427-437. https://doi.org/10.1056/NEJMoa2410027
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389(24):2221-2232. https://doi.org/10.1056/NEJMoa2307563
Lingvay I, Deanfield J, Kahn SE, et al. Semaglutide and cardiovascular outcomes by baseline HbA1c and change in HbA1c in people with overweight or obesity but without diabetes in SELECT. Diabetes Care. 2024;47(8):1360-1369. https://doi.org/10.2337/dc24-0764
Deanfield J, et al. Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet. 2025;406:2257-2268. https://doi.org/10.1016/S0140-6736(25)01375-3
Colhoun HM, et al. Mediation analysis of the cardiovascular effect of semaglutide in SELECT. Eur Heart J. 2026. Summary: Healio, "CV benefits of semaglutide appear to be related to more than weight loss" (October 2026).
Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). N Engl J Med. 2024;391(2):109-121. https://doi.org/10.1056/NEJMoa2403347
Mann JFE, Buse JB, Idorn T, et al. Potential kidney protection with liraglutide and semaglutide: exploratory mediation analysis. Diabetes Obes Metab. 2021;23(9):2058-2066. https://doi.org/10.1111/dom.14443
Mitchell JL, Lyons HS, Walker JK, et al. The effect of GLP-1RA exenatide on idiopathic intracranial hypertension: a randomized clinical trial. Brain. 2023;146(5):1821-1830. https://doi.org/10.1093/brain/awad003
Botfield HF, Uldall MS, Westgate CSJ, et al. A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus. Sci Transl Med. 2017;9(404):eaan0972. https://doi.org/10.1126/scitranslmed.aan0972
Klausen MK, Jensen ME, Møller M, et al. Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight. 2022;7(19):e159863. https://insight.jci.org/articles/view/159863
Hendershot CS, Bremmer MP, Paladino MB, et al. Once-weekly semaglutide in adults with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry. 2025. https://doi.org/10.1001/jamapsychiatry.2024.4789
Schacht JP, Sakai JT, Raymond K, Shelton R. Oral semaglutide for alcohol use disorder: a randomized clinical trial. Am J Psychiatry. Published online July 29, 2026. https://doi.org/10.1176/appi.ajp.20260003
Klausen MK, et al. Once-weekly semaglutide versus placebo in patients with alcohol use disorder and comorbid obesity (SEMALCO): a randomised, double-blind, placebo-controlled trial. Lancet. 2026;407(10540):1687-1698. https://doi.org/10.1016/S0140-6736(26)00305-3

Lean mass loss on GLP-1 drugs, and the myostatin drugs trying to prevent it

2026-11-05T00:00:00Z

Rapid weight loss costs muscle as well as fat. In the DEXA substudy of STEP 1 (140 participants), people on semaglutide lost 15 percent of body weight over 68 weeks, and roughly 40 percent of what they lost was lean mass [1]. In the SURMOUNT-1 DEXA substudy (160 participants), about 25 percent of the weight lost on tirzepatide was lean mass, the same proportion as on placebo [2]. Lean mass on a scan includes water, glycogen, and organ tissue as well as muscle, so these numbers overstate muscle loss, but they are not zero. For an older adult, the trade can mean weaker legs, worse balance, and less reserve in an illness. Two responses exist. The first is behavioral: resistance training and adequate protein while losing weight. In a 2018 meta-analysis of six trials in older adults with obesity, resistance training prevented 93.5 percent of the lean mass loss caused by calorie restriction [3], and a 2016 meta-analysis found older adults on higher-protein diets kept more lean mass during weight loss [4]. The second response is pharmacologic, and it is producing a strange result.

The target

Myostatin is a signal muscle cells release to limit their own growth. Mice with the gene knocked out have individual muscles two to three times normal weight [5], and a child born in 2000 with a loss-of-function mutation in both copies had gross muscle hypertrophy and no detectable myostatin in his blood [6]. That made the pathway an obvious drug target. Blocking it should, in theory, preserve or add muscle. The open question has always been whether the added mass does anything.

What they did: EMBRAZE

Apitegromab is an antibody that blocks myostatin activation. In the Phase 2 EMBRAZE trial, 102 adults with overweight or obesity took tirzepatide (up to 15 mg weekly) for weight loss and were randomized to apitegromab 10 mg/kg every four weeks or placebo for 24 weeks [7]. Both groups lost a similar amount of weight, 12.3 percent with apitegromab and 13.4 percent with placebo [8]. The composition differed. The apitegromab group lost 1.6 kg of lean mass and 8.5 kg of fat; the placebo group lost 3.5 kg of lean mass and 8.0 kg of fat. Lean mass was 14.6 percent of the weight lost on the drug, versus 30.2 percent on placebo, a difference of 1.9 kg (p = 0.001) [7, 8].

What they found

By body composition, the drug did its job. By function, it did not show up. Grip strength and sit-to-stand tests were exploratory endpoints, and neither differed significantly between groups at 24 weeks; the authors also reported no clear improvement in cardiometabolic measures [7]. An extra 1.9 kg of preserved lean mass bought no measurable strength over six months. Possible explanations include the short trial, the relatively young participants, and the gap between DEXA lean mass and actual contractile muscle.

The pattern repeats: bimagrumab

Bimagrumab blocks the activin type II receptors that myostatin and related signals act through. In the Phase 2 BELIEVE trial, 507 adults with obesity were randomized across nine arms for 48 weeks [9]. At 48 weeks, high-dose bimagrumab with semaglutide 2.4 mg produced 17.8 kg of weight loss, versus 14.2 kg on semaglutide alone, 9.3 kg on bimagrumab alone, and 3.3 kg on placebo. About 92 percent of the combination group's loss was fat, against 76 percent for semaglutide alone, and bimagrumab alone raised lean mass by about 2.5 percent while fat fell [9, 10]. The trial's primary endpoint was weight; no functional benefit has been reported. Side effects were higher with bimagrumab: muscle spasms and acne were more common, and 14 to 21 percent of bimagrumab-treated participants stopped for adverse events, versus 3.6 percent on placebo [9].

Earlier bimagrumab trials in muscle disease and in frail older adults tell the same story. A 14-patient pilot in sporadic inclusion body myositis reported more thigh muscle on MRI and a better six-minute walk at 16 weeks [11], but the 52-week RESILIENT trial that followed did not improve six-minute walk distance at any dose [12], and its two-year extension found no mobility benefit either [13]. In 180 adults aged 70 and older with sarcopenia, six months of bimagrumab raised lean mass by 7 percent versus 1 percent on placebo, yet the physical performance score (1.34 versus 1.03 points), gait speed (0.14 versus 0.11 m/s), and six-minute walk (24.6 versus 14.3 m) all improved similarly in both groups, which both received diet advice and a home exercise program [14].

What the scan does not measure

A DEXA scan reports lean mass, which includes water and connective tissue along with contractile muscle. Strength depends on fiber quality, nervous system recruitment, and tendons, none of which the scan reports. Across every myostatin-pathway trial published so far, the drug has added or preserved mass on the scan without improving a functional endpoint such as chair stands, gait speed, grip strength, or walk distance. For patients losing weight now, resistance training and protein have functional evidence behind them [3, 4]. A muscle drug will have earned a place when it improves one of those functional measures in a trial designed to detect it.

Sources

Wilding JPH, Batterham RL, Calanna S, et al. Impact of semaglutide on body composition in adults with overweight or obesity: exploratory analysis of the STEP 1 study. J Endocr Soc. 2021;5(Suppl 1):A16-A17. https://doi.org/10.1210/jendso/bvab048.030
Look M, et al. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight. Diabetes Obes Metab. 2025;27:2720. https://doi.org/10.1111/dom.16275
Sardeli AV, Komatsu TR, Mori MA, Gáspari AF, Chacon-Mikahil MPT. Resistance training prevents muscle loss induced by caloric restriction in obese elderly individuals: a systematic review and meta-analysis. Nutrients. 2018;10(4):423. https://doi.org/10.3390/nu10040423
Kim JE, O'Connor LE, Sands LP, Slebodnik MB, Campbell WW. Effects of dietary protein intake on body composition changes after weight loss in older adults: a systematic review and meta-analysis. Nutr Rev. 2016;74(3):210-224. https://doi.org/10.1093/nutrit/nuv065
McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387(6628):83-90. https://doi.org/10.1038/387083a0
Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;350(26):2682-2688.
Pratley RE, et al. Apitegromab with tirzepatide for preservation of lean mass during weight loss (EMBRAZE): a randomized phase 2 trial. Nat Med. 2026. https://doi.org/10.1038/s41591-026-04440-4
Scholar Rock. Scholar Rock reports positive Phase 2 EMBRAZE trial results demonstrating statistically significant preservation of lean mass with apitegromab during tirzepatide-induced weight loss. Press release, June 18, 2025. https://www.businesswire.com/news/home/20250618254394/en/
Heymsfield SB, Aronne LJ, Montgomery P, et al. Bimagrumab plus semaglutide alone or in combination for the treatment of obesity: a randomized phase 2 trial (BELIEVE). Nat Med. 2026. https://doi.org/10.1038/s41591-026-04204-0
Pennington Biomedical Research Center. Combination GLP-1 therapy shows fat mass loss while preserving lean mass in adults with obesity. Press release, March 2026. https://www.pbrc.edu/news/media/2026/semaglutide_and_bimagrumab.aspx
Amato AA, Sivakumar K, Goyal N, et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology. 2014;83(24):2239-2246. https://doi.org/10.1212/WNL.0000000000001070
Hanna MG, Badrising UA, Benveniste O, et al. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2019;18(9):834-844. https://doi.org/10.1016/S1474-4422(19)30200-5
Amato AA, Hanna MG, Machado PM, et al. Efficacy and safety of bimagrumab in sporadic inclusion body myositis: long-term extension of RESILIENT. Neurology. 2021;96(12):e1595-e1607. https://doi.org/10.1212/WNL.0000000000011626
Rooks D, Swan T, Goswami B, et al. Bimagrumab vs optimized standard of care for treatment of sarcopenia in community-dwelling older adults: a randomized clinical trial. JAMA Netw Open. 2020;3(10):e2020836. https://doi.org/10.1001/jamanetworkopen.2020.20836

Gray-market peptides, retatrutide, and the difference between a drug and a vial

2026-11-06T00:00:00Z

Two products can share a name and have almost nothing else in common. One is a molecule moving through FDA trials, with verified manufacturing and dose-finding studies. The other is a vial of powder sold online under the same name, made by an unknown facility. Most of the confusion in the current peptide market comes from treating those two things as one.

Where the compounds came from

The common gray-market peptides have different histories, and few of them match the story usually told about them.

BPC-157 came out of an academic lab, not a drug company. Predrag Sikiric's group at the University of Zagreb described it in 1993 as a fragment of a protein found in human gastric juice [1]. A 2026 investigation co-published by STAT and Undark reported that the group has never published key details of the discovery, including the sequence of the parent protein, which makes the original isolation work impossible for others to reproduce [2]. A Croatian company, Pliva, ran small ulcerative colitis trials of the peptide in the 2000s; the results appeared only as conference abstracts and were never published in full [2, 3].

TB-500 is a short synthetic fragment of thymosin beta-4 (the acetylated residues 17 to 23, the actin-binding region) [4]. A small biotech, RegeneRx, ran Phase 2 trials of the full-length protein for pressure ulcers, venous stasis ulcers and dry eye [5, 6]. Those trials tested the whole protein, not the seven-amino-acid fragment sold as TB-500.

CJC-1295 is the one that did go through a company program. ConjuChem, a small Canadian biotech, published Phase 1 data in 2006: in healthy adults a single injection raised growth hormone 2- to 10-fold for six days or more and IGF-1 1.5- to 3-fold for 9 to 11 days [7]. A Phase 2 trial in HIV-related visceral obesity was stopped in July 2006 after a participant died at a site in Argentina [8]. The Phase 2 results were never published.

None of this is evidence that a compound works, and none of it is evidence that it does not. It is evidence that the work was not finished.

What the approved pipeline shows

Retatrutide is the clearest current example of the difference. It is Eli Lilly's drug acting on GLP-1, GIP and glucagon receptors. In the Phase 2 trial published in 2023, 338 adults with obesity or overweight were randomized to weekly retatrutide or placebo for 48 weeks; the 12 mg group lost a mean 24.2 percent of body weight against 2.1 percent on placebo [9]. In 2026 Lilly reported Phase 3 results: in TRIUMPH-1, 2,339 participants were randomized to 4, 9 or 12 mg or placebo, and weight fell 28.3 percent at 80 weeks on 12 mg against 2.2 percent on placebo [10]. Those Phase 3 numbers are sponsor-reported topline results presented at the American Diabetes Association meeting in June 2026; the full peer-reviewed papers had not appeared as of this writing. Lilly said in its second-quarter 2026 report that it plans to file for approval in the first quarter of 2027 [11].

So, as of November 2026, retatrutide is not approved. It cannot be prescribed, and no licensed pharmacy dispenses it.

Product sold today under that name therefore comes from research chemical suppliers, many overseas, outside any inspection regime. Independent testing of this market has found what one would expect. In a 2024 study, researchers bought semaglutide from six online sellers that did not require a prescription; the vials were labeled 99 percent pure, measured purity was 7.7 to 14.4 percent, and every sample contained endotoxin [12]. A 2026 preprint analyzed 6,285 lab reports on 14 peptides from 203 manufacturers, submitted to a public testing platform between December 2024 and April 2026, and found that 41.6 percent failed on dose accuracy, purity or identity even against the looser standard applied to compounded drugs [13]. That preprint has not been peer reviewed, and its samples came from a voluntary testing program, not random purchases, so the true failure rate across the market could be higher or lower. Seller-issued certificates of analysis are produced by the sellers.

The evidence problem underneath

Even a genuine vial would leave the central problem untouched. For most of these compounds, human efficacy data do not exist. A 2025 systematic review of BPC-157 in HSS Journal found 36 studies published between 1993 and 2024: 35 were animal studies and one was an uncontrolled human chart review. The authors wrote that there are no clinical safety data in humans [14]. No randomized, placebo-controlled trial of BPC-157 has been published in full.

Growth hormone secretagogues have more human data, but of a narrow kind. The CJC-1295 trial measured hormone levels over 28 to 49 days and nothing else [7]. The one published Phase 2 outcome trial of ipamorelin, in 114 patients recovering from bowel surgery, found no difference from placebo in time to tolerating a meal [15]. Raising growth hormone or IGF-1 is a lab result; healing tissue, building muscle or extending health is an outcome, and the outcome trials have not been done.

The FDA's position has moved in both directions. In September 2023 the agency placed BPC-157, CJC-1295, ipamorelin and other peptides in Category 2 of its interim list for 503A compounding, citing immunogenicity risk, peptide-related impurities and limited human safety data; Category 2 means compounding pharmacies may not use them [16]. CJC-1295 and ipamorelin were later removed from Category 2 after their nominators withdrew, and in December 2024 the Pharmacy Compounding Advisory Committee voted against adding any form of CJC-1295 to the compounding list [17]. In April 2026 the FDA removed twelve peptides, including BPC-157 and TB-500, from Category 2, again because nominations were withdrawn, and sent them to the committee for review [18]. On July 23, 2026 the committee voted 8 to 6 to recommend adding BPC-157 and TB-500 to the 503A list, against the recommendation of FDA's own reviewers, who had concluded the evaluation criteria weighed against both [19, 20]. The vote is advisory. As of November 2026 the FDA has not added either peptide to the list, and until it does, no compounding pharmacy may legally prepare them. Supply remains with unregulated sellers.

Interpretation

Three questions separate a medication from an experiment: has it been tested in humans, at this dose, for this condition; who manufactured this batch and what independent testing verifies its contents; and what outcome, measured how, would count as it working. Approved drugs answer all three. The gray market, at present, answers none of them reliably. Retatrutide may well become an approved drug in 2027 or 2028. A vial bought today has no connection to that trial program beyond the name on the label.

Sources

Sikiric P, Petek M, Rucman R, et al. A new gastric juice peptide, BPC: an overview of the stomach-stress-organoprotection hypothesis and beneficial effects of BPC. Journal of Physiology (Paris), 1993;87(5):313-327.
Talpos S. BPC-157 peptide: a secretive Croatian researcher's 50-year quest. STAT, co-published with Undark, June 1, 2026. https://www.statnews.com/2026/06/01/bpc-157-researcher-predrag-sikiric-addesses-skeptics-questions/
Croatian researchers thrust into limelight as their 1990s peptide discovery goes mainstream in the US. Chemistry World, 2026. https://www.chemistryworld.com/news/croatian-researchers-thrust-into-limelight-as-their-1990s-peptide-discovery-goes-mainstream-in-the-us/4023660.article
TB-500 (thymosin beta-4 fragment 17-23, Ac-LKKTETQ), CAS 885340-08-9. Chemical supplier entry, EvitaChem. https://evitachem.com/product/evt-242849
RegeneRx reports Phase II pressure ulcer trial results. Fierce Biotech. https://www.fiercebiotech.com/biotech/regenerx-reports-phase-ii-pressure-ulcer-trial-results
RegeneRx reports Phase II venous stasis trial results. Fierce Biotech, 2009. https://www.fiercebiotech.com/biotech/regenerx-reports-phase-ii-venous-stasis-trial-results
Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. Journal of Clinical Endocrinology and Metabolism, 2006;91(3):799-805. PMID 16352683.
Lipodystrophy study halted after patient death. aidsmap, July 2006. https://www.aidsmap.com/news/jul-2006/lipodystrophy-study-halted-after-patient-death (trial registration NCT00267527).
Jastreboff AM, Kaplan LM, Frias JP, et al. Triple-hormone-receptor agonist retatrutide for obesity: a Phase 2 trial. New England Journal of Medicine, 2023;389(6):514-526. https://doi.org/10.1056/NEJMoa2301972
TRIUMPH-1: retatrutide substantially lowers weight, BMI in patients with obesity or overweight (ADA Scientific Sessions, June 6, 2026). HCPLive, 2026. https://hcplive.com/view/triumph-1-retatrutide-substantially-lowers-weight-bmi-in-patients-with-obesity-or-overweight
Eli Lilly and Company. Second-quarter 2026 financial results (Form 8-K), August 5, 2026. https://www.sec.gov/Archives/edgar/data/0000059478/000005947826000077/q226lillysalesandearningsp.htm
Ashraf AR, et al. Safety and risk assessment of no-prescription online semaglutide purchases. Journal of Medical Internet Research, 2024;26:e65440. https://jmir.org/article/export/ris/jmir_v26i1e65440
Mendias CL, Awan T. Evaluation of research grade peptides marketed directly to consumers reveals extensive variability in purity and measured abundance. Preprints.org, April 2026 (not peer reviewed). https://doi.org/10.20944/preprints202604.1748.v1
Vasireddi N, et al. Emerging use of BPC-157 in orthopaedic sports medicine: a systematic review. HSS Journal, 2025. PMID 40756949. https://pmc.ncbi.nlm.nih.gov/articles/PMC12313605/
Beck DE, Sweeney WB, McCarter MD; Ipamorelin 201 Study Group. Prospective, randomized, controlled, proof-of-concept study of the ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. International Journal of Colorectal Disease, 2014;29(12):1527-1534. https://doi.org/10.1007/s00384-014-2030-8
FDA. Certain bulk drug substances for use in compounding that may present significant safety risks (interim 503A bulks list, Category 2). https://www.fda.gov/drugs/human-drug-compounding/certain-bulk-drug-substances-use-compounding-may-present-significant-safety-risks
FDA. Pharmacy Compounding Advisory Committee, December 4, 2024: briefing document on CJC-1295 and summary minutes (approved February 21, 2025). https://www.fda.gov/media/183945/download and https://fda.gov/media/185642/download
Mondaq. FDA signals potentially evolving stance toward compounding of certain peptides (Category 2 removals announced April 15, 2026). https://www.mondaq.com/unitedstates/healthcare/1785274/fda-signals-potentially-evolving-stance-toward-compounding-of-certain-peptides
FDA. Briefing document, Pharmacy Compounding Advisory Committee meeting July 23-24, 2026 (BPC-157, KPV, TB-500, MOTS-c). https://www.fda.gov/media/193343/download
FDA panel backs 6 peptides for compounding. American Journal of Managed Care, July 2026. https://www.ajmc.com/view/fda-panel-backs-6-peptides-for-compounding

Prioritizing health interventions: what an N of 1 cannot tell you

2026-11-07T00:00:00Z

Bryan Johnson, a technology founder, was reported in 2023 to spend about two million dollars a year testing interventions on himself: timed meals, dozens of supplements, light therapy, hyperbaric oxygen, and frequent measurement of a long list of biomarkers [1]. His published results raise a methodological problem that applies well beyond one person.

The design problem

A self-experiment with one subject and dozens of simultaneous interventions cannot identify which intervention did what. There is no control group, no blinding, and no way to separate the exotic items from the ordinary ones running alongside them: regular sleep, daily training, a controlled diet, and no alcohol. Those habits carry strong evidence in population data on their own. If a composite biological age score improves, the design cannot say which input moved it. Medicine stopped accepting the single-case testimonial as evidence of efficacy for this reason, and the limit applies to a careful, well-funded single case as much as to a careless one.

What the population data say to do first

Prioritization becomes possible when interventions are ranked by measured effect size in large populations.

Social connection. A 2010 meta-analysis of 148 studies covering 308,849 people, followed for an average of 7.5 years, found that people with stronger social relationships had a 50 percent greater likelihood of survival (odds ratio 1.50, 95% CI 1.42 to 1.59). The authors judged the effect comparable to quitting smoking and larger than the effects of obesity or physical inactivity [2]. Isolation carries a measured risk in the same range as the standard cardiovascular risk factors.

Cardiorespiratory fitness and muscle. In a cohort of 122,007 adults who had treadmill testing at the Cleveland Clinic between 1991 and 2014, all-cause mortality fell step by step with fitness; the fittest group had an adjusted hazard ratio of 0.20 compared with the least fit, and the authors reported that low fitness was associated with mortality as strongly as, or more strongly than, smoking, coronary disease or diabetes [3]. In the PURE study of 139,691 adults across high-, middle- and low-income countries, each 5 kg lower grip strength was associated with a 16 percent higher risk of death over a median of four years, and grip strength predicted all-cause and cardiovascular death better than systolic blood pressure did [4]. Both measures are observational; the PURE authors called for trials testing whether improving strength lowers mortality, and those trials have not been done. Both are also trainable, which the exotic items on a protocol list cannot claim with the same evidence.

The standard risk factors. In the INTERHEART case-control study of 15,152 first heart attacks and 14,820 controls in 52 countries, nine modifiable factors (abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial stress, low fruit and vegetable intake, alcohol, and lack of regular physical activity) accounted for 90 percent of the population attributable risk of myocardial infarction in men and 94 percent in women [5]. That is a case-control estimate, not proof that correcting each factor prevents its share of events, but each of those factors has intervention trials with outcome data behind it. Sleep was not measured in INTERHEART and belongs on the list on the strength of other evidence.

Interpretation

None of this rules out benefit from the long tail of interventions: hyperbaric oxygen, red light, plasma exchange, and the rest. It sets the order of operations. A protocol built on poor sleep, no training, and untreated blood pressure spends effort on the smallest terms in the equation. The sequence the data support is to fix the factors with the largest measured effects, measure the result, and treat everything after that as optional experimentation held with low confidence. A protocol that a person with a job and a family cannot follow also fails a second test, adherence over years, which is where most of these outcomes are decided.

Sources

Fortune. Bryan Johnson is spending $2 million a year to stay young forever. July 14, 2023. https://www.fortune.com/2023/07/14/bryan-johnson-spending-2-million-young-forever
Holt-Lunstad J, Smith TB, Layton JB. Social relationships and mortality risk: a meta-analytic review. PLoS Medicine, 2010;7(7):e1000316. https://doi.org/10.1371/journal.pmed.1000316
Mandsager K, Harb S, Cremer P, Phelan D, Nissen SE, Jaber W. Association of cardiorespiratory fitness with long-term mortality among adults undergoing exercise treadmill testing. JAMA Network Open, 2018;1(6):e183605. https://doi.org/10.1001/jamanetworkopen.2018.3605
Leong DP, Teo KK, Rangarajan S, et al. Prognostic value of grip strength: findings from the Prospective Urban Rural Epidemiology (PURE) study. The Lancet, 2015;386(9990):266-273. https://doi.org/10.1016/S0140-6736(14)62000-6
Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. The Lancet, 2004;364(9438):937-952. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2011/01/24/22/24/INTERHEART

Keto, fasting, and energy balance: positions that changed with the data

2026-11-08T00:00:00Z

Few areas of nutrition have reversed as publicly as low-carbohydrate and fasting strategies. Positions held with confidence a decade ago, that ketogenic diets drive fat loss through insulin suppression, that extended fasts are necessary for cellular cleanup, that metformin is a longevity drug for healthy people, have each been revised as controlled data arrived. The revisions are more instructive than the original claims.

What the feeding studies showed

The metabolic ward, where every calorie eaten and expended is measured, is where the insulin model of obesity has been put to a controlled test. In a National Institutes of Health study published in 2016, 17 men with overweight or obesity lived on a ward and ate a high-carbohydrate baseline diet for four weeks, then switched to a ketogenic diet with the same calories for another four weeks [1]. Energy expenditure measured in the respiratory chamber rose briefly after the switch, by roughly 100 kcal a day at first, and averaged about 57 kcal a day higher across the ketogenic phase. Body fat loss did not speed up; it slowed during the ketogenic weeks, and the men lost fat-free mass as protein use rose [1]. A later reanalysis by other investigators argued that a second method, doubly labeled water, showed a larger rise in expenditure outside the chamber; Hall's group replied that the calculation did not account for the energy imbalance each diet produced [2]. Either way, the measured difference was tens of calories, not the hundreds the insulin model predicted, and fat loss did not accelerate.

A second ward study from the same group, published in 2019, isolated the variable most diets change without saying so. Twenty adults alternated between an ultra-processed diet and an unprocessed diet for two weeks each, with the meals matched for presented calories, sugar, fat, fiber, and macronutrients, and the participants ate as much or as little as they wanted [3]. On the ultra-processed diet they ate about 508 kcal more a day and gained 0.9 kg; on the unprocessed diet they lost 0.9 kg [3]. The macronutrient ratio was held constant, and intake still moved by 500 calories a day, so food form carried the effect.

Fasting, sized correctly

Time-restricted eating has fared similarly under testing. In the TREAT trial, published in 2020, 141 adults with overweight or obesity were randomized to either a 16:8 eating window (noon to 8 pm) or three structured meals a day for 12 weeks; 116 provided data [4]. The time-restricted group lost 0.94 kg, but the difference from the control group, 0.26 kg, was not significant. In a subset of 50 participants who had body composition measured in person, appendicular lean mass index fell more in the time-restricted group (between-group difference 0.16 kg/m², P = .005), which the authors flagged as a concern needing follow-up [4].

Smaller, shorter trials of early time-restricted eating have shown metabolic effects in a narrow setting. In a five-week crossover trial, eight men with prediabetes ate all their food in a six-hour window ending before 3 pm, with calories set to hold weight steady; insulin sensitivity, blood pressure, and oxidative stress markers improved compared with a 12-hour window [5]. That is a supervised, weight-stable, eight-person study, and its result has not been shown at scale.

Human data on autophagy during fasting are thinner than the popular account suggests. In one study, volunteers fasted for up to four days; autophagy activation in their blood cells was detectable only in neutrophils, and measuring the change in flux required culturing the cells with a protease inhibitor [6]. Most of what is said about fasting and autophagy comes from mouse and cell work. None of this supports multi-day fasts as a default practice for older adults, for whom lean mass is the resource a fast spends first.

Metformin in people without diabetes

The metformin case ran the same course. In a 12-week trial published in 2019, 53 older adults (mean age about 62) were randomized to metformin or placebo during supervised aerobic exercise training [7]. Metformin blocked the rise in skeletal muscle mitochondrial respiration that exercise produced in the placebo group, and whole-body insulin sensitivity did not improve on average in the metformin group because some participants improved and others got worse [7]. The authors concluded that more work was needed before metformin could be recommended to slow aging in healthy people.

Interpretation

The current evidence supports a plainer account. Diets work when they reduce intake in a way a person can sustain, and ketogenic diets are one such tool. They have a documented role in type 2 diabetes: in a one-year, non-randomized study of 262 adults on a very low-carbohydrate program with remote medical supervision, HbA1c, weight, and diabetes medication use all fell, with no change in 87 usual-care controls; the study was funded by the company running the program and the groups were not randomized [8]. Fasting windows are a scheduling tool with modest measured effects on weight. In both cases, the effect sizes in controlled studies are small and the adherence effects are large, and the ward data set the ceiling on what a diet's mechanism can deliver.

Sources

Hall KD, Chen KY, Guo J, et al. Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men. American Journal of Clinical Nutrition, 2016;104(2):324-333. https://doi.org/10.3945/ajcn.116.133561
Hall KD, et al. Mystery or method? Evaluating claims of increased energy expenditure during a ketogenic diet. PLoS ONE, 2019. https://pmc.ncbi.nlm.nih.gov/articles/PMC6901214
Hall KD, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metabolism, 2019. https://doi.org/10.1016/j.cmet.2019.05.008
Lowe DA, et al. Effects of time-restricted eating on weight loss and other metabolic parameters in women and men with overweight and obesity: the TREAT randomized clinical trial. JAMA Internal Medicine, 2020;180(11):1491-1499. https://doi.org/10.1001/jamainternmed.2020.4153
Sutton EF, et al. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metabolism, 2018. https://doi.org/10.1016/j.cmet.2018.04.010
Pietrocola F, et al. Metabolic effects of fasting on human and mouse blood in vivo. Autophagy, 2017;13(3):567-578. https://doi.org/10.1080/15548627.2016.1271513
Konopka AR, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell, 2019;18(1):e12880. https://doi.org/10.1111/acel.12880
Hallberg SJ, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Therapy, 2018. https://doi.org/10.1007/s13300-018-0373-9

NAD+ precursors: blood levels rise, outcomes have not followed

2026-11-09T00:00:00Z

NAD+ is a molecule mitochondria use in the core reactions that produce ATP, and its levels in several tissues decline with age in animal studies. That single fact supports a large market: intravenous NAD+ infusions at clinics, and oral precursors, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), sold as supplements. The human trial record is now large enough to summarize.

What the trials did and found

Nicotinamide riboside. In the first placebo-controlled human trial, published in 2018, 30 healthy adults aged 55 to 79 were randomized to NR 500 mg twice a day or placebo in a six-week crossover design, and 24 completed it [1]. NR raised blood NAD+ by about 60 percent and was well tolerated. In an exploratory analysis, systolic blood pressure and arterial stiffness were lower on NR in the 13 participants who started with elevated blood pressure or stage 1 hypertension. The authors described the study as a pilot and said a larger trial was needed before any claim about blood pressure could be made [1]. A second six-week crossover trial, published in 2020, gave NR 1000 mg a day to 13 adults with overweight or obesity and measured insulin sensitivity by clamp, muscle mitochondrial function from biopsies, liver and muscle fat, cardiac function, and ambulatory blood pressure. Muscle acetylcarnitine rose, and nothing else changed: no improvement in insulin sensitivity, mitochondrial function, blood pressure, or inflammation markers [2].

NMN. In a 10-week randomized trial published in 2021, 25 postmenopausal women with prediabetes and overweight or obesity took NMN 250 mg a day (n = 13) or placebo (n = 12). Insulin-stimulated glucose disposal in muscle, measured by clamp, improved with NMN, along with muscle insulin signaling markers. Blood glucose, blood pressure, lipids, liver insulin sensitivity, liver fat, and inflammation markers did not change [3]. It remains one of the few positive functional findings in the precursor literature, in a small and specific population, and one of the authors is an inventor on a patent application related to NMN.

Newer trials and pooled analyses. Trials since 2022 have added functional endpoints and have mostly come back null. A 24-week placebo-controlled trial in 14 men aged 65 and older with diabetes and reduced grip strength or walking speed found no improvement in either measure with NMN 250 mg a day [4]. A 12-week industry-funded trial in healthy older men reported nominal gains in gait speed and left-hand grip strength that the authors said needed validation in larger studies [5]. A 2025 meta-analysis of randomized trials of NMN or NR in adults with a mean age of 60 or older found no effect on muscle mass, handgrip strength, gait speed, or chair-stand time, with one exception: a longer six-minute walk distance with NR in people with peripheral artery disease [6]. A 2024 meta-analysis of eight NMN trials (342 adults, 14 days to 12 weeks) found no benefit on fasting glucose, insulin, HbA1c, insulin resistance, or lipids [7].

Lifespan data. In mice, the National Institute on Aging's Interventions Testing Program, which runs lifespan studies in genetically heterogeneous mice, found no lifespan extension from NR in either sex [8]. No human trial of any precursor has reported lifespan, healthspan, dementia, or cardiovascular events as an endpoint.

The measurement gap

Two structural problems run through this literature. First, there is no validated clinical test of tissue NAD+ status. Blood levels respond to supplementation, but blood is not the tissue of interest, and no trial has shown that a blood level predicts a clinical outcome. A 2026 study of seven cohorts (303 participants) that used a pre-validated mass spectrometry assay found that whole-blood NAD+ did not vary with age or with exercise and diet interventions, and that measured levels were highly sensitive to how samples were stored and handled; the authors attributed much of the earlier conflicting literature to those handling artifacts [9]. The National Institute on Aging has an open funding call for standardized methods to measure NAD+ in clinical trials, which is a plain statement that none exists yet.

Second, infused NAD+ does not reach cells as NAD+. Cell-surface enzymes (CD38, CD157, CD73, NPP1) break extracellular NAD+ down into nicotinamide, NMN, and NR, and it is those breakdown products that cells take up and use to rebuild NAD+ inside [10]. Cell culture work with isotope-labeled compounds showed that NMN itself is converted to NR outside the cell before uptake [11]. The infusion therefore delivers the same building blocks the oral precursors do, at infusion prices.

Interpretation

Precursors reliably move a blood number. Across trials, they have not reliably moved strength, walking speed, aerobic capacity, insulin sensitivity in general populations, or any hard endpoint, and the one positive insulin finding sits in a single 25-person trial in one defined group. A real biochemical effect without demonstrated clinical benefit is the profile of an unproven product, and when time and money are limited, interventions with outcome data come first.

Sources

Martens CR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 2018. https://doi.org/10.1038/s41467-018-03421-7
Remie CME, et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. American Journal of Clinical Nutrition, 2020;112(2):413-426. https://doi.org/10.1093/ajcn/nqaa072
Yoshino M, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 2021;372:1224-1229. https://doi.org/10.1126/science.abe9985
Akasaka H, et al. Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance. Geriatrics & Gerontology International, 2023;23(1):38-43. https://pubmed.ncbi.nlm.nih.gov/36443648/
Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. npj Aging, 2022. https://doi.org/10.1038/s41514-022-00084-z
Prokopidis K, et al. The effect of nicotinamide mononucleotide and riboside on skeletal muscle mass and function: a systematic review and meta-analysis. Journal of Cachexia, Sarcopenia and Muscle, 2025;16(3):e13799. https://doi.org/10.1002/jcsm.13799
Chen F, et al. Effects of nicotinamide mononucleotide on glucose and lipid metabolism in adults: a systematic review and meta-analysis of randomised controlled trials. Current Diabetes Reports, 2024. https://doi.org/10.1007/s11892-024-01557-z
Harrison DE, et al. 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging Cell, 2021;20(5):e13328. https://doi.org/10.1111/acel.13328
Trętowicz et al. Human whole-blood NAD+ levels do not vary with age or lifestyle interventions. Nature Metabolism, 2026. https://doi.org/10.1038/s42255-026-01537-5
Enzymology of extracellular NAD metabolism. Cellular and Molecular Life Sciences, 2021. https://doi.org/10.1007/s00018-020-03742-1
Ratajczak J, et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nature Communications, 2016;7:13103. https://doi.org/10.1038/ncomms13103

GLP-1 drugs, PCOS, and the fertility effect that needs a conversation

2026-11-10T00:00:00Z

Polycystic ovary syndrome is usually described as a reproductive condition. Its drivers are largely metabolic: insulin resistance and excess weight suppress ovulation, cycles become irregular or stop, and fertility falls. Weight loss has been first-line advice for overweight women with PCOS for this reason, in the 2013 Endocrine Society guideline and again in the 2023 international guideline [1, 2]. GLP-1 drugs produce that weight loss reliably, and a less discussed consequence is pregnancy in women who believed they could not conceive.

Why the risk is easy to miss

Three assumptions collide. The patient assumes irregular cycles mean infertility, an assumption that may have held for years. Cycle-based contraception, if used, is calibrated to the old pattern. And the prescriber, often in a brief telehealth visit, may never ask about contraception.

The trial data show cycles changing within months of starting treatment. A 26-week randomized trial of liraglutide in 72 women with PCOS found more bleeding episodes in the treated group than with placebo, alongside 5.2 kg more weight loss [3]. A 2023 meta-analysis of 11 randomized trials (840 women) found better menstrual regularity and a higher natural pregnancy rate with GLP-1 drugs (relative risk 1.72) [4]. Ovulation itself was not measured in most of these trials, so the exact timing of its return is not known [4]. What the trials do show is consistent with fertility returning before any weight goal is reached, and a first ovulation can come before a woman notices any change in her cycle.

What the reports show

News coverage began in 2024, when women posted on TikTok about unplanned pregnancies on semaglutide and tirzepatide and the term "Ozempic babies" spread [5]. The published data since then are observational.

An Australian general-practice study in the Medical Journal of Australia followed 18,010 women aged 18 to 49 who were first prescribed a GLP-1 drug between 2011 and 2022. At the time of the prescription, 21.2 percent had documented contraception, and 2.2 percent were pregnant within six months [6]. By 2022, about nine in ten new prescriptions in this age group went to women without diabetes [6].

On outcomes, a 2026 meta-analysis in the journal Med pooled 10 observational studies covering 2,118,215 pregnancies, 8,325 of them with GLP-1 exposure in the six months before a positive pregnancy test. It found no detectable increase in miscarriage, stillbirth, congenital anomalies, or preterm birth. The authors wrote that this is not evidence of safety in pregnancy and does not change the advice to stop before a planned pregnancy [7]. A 2026 claims analysis of 3,572 US pregnancies in Annals of Internal Medicine compared continuing a GLP-1 drug into the first trimester with stopping it and found similar rates of non-live birth (29.7 versus 27.1 percent), with estimates for major malformations too imprecise to settle the question [8].

The same physiology has a welcome side. For women with PCOS who want to conceive, these drugs accomplish what metformin did weakly. In a 2015 meta-analysis of 12 randomized trials, metformin added to lifestyle change lowered BMI by 0.73 kg/m² over six months compared with lifestyle alone, and metformin by itself did no better than lifestyle plus placebo [9].

What planning requires

The FDA labels for Ozempic and Wegovy advise stopping semaglutide at least two months before a planned pregnancy because of its long washout period; animal studies showed fetal harm, and the drugs are not recommended in pregnancy [10, 11]. Tirzepatide carries a separate warning: it can reduce absorption of oral contraceptives, so the label advises switching to a non-oral method or adding a barrier method for four weeks after starting and for four weeks after each dose increase [12].

Folate matters on the same timeline. The neural tube closes within the first month after conception, around day 28, usually before a pregnancy is recognized [13]. This is why the CDC advises 400 micrograms of folic acid daily for all women aged 15 to 45 who could become pregnant, starting at least a month before conception, and not only for those actively trying [14]. The MRC Vitamin Study, a randomized trial published in The Lancet in 1991, showed a 72 percent reduction in neural tube defects with 4 mg of folic acid daily in women who had a previous affected pregnancy (relative risk 0.28) [15]. The timing argument has not changed since.

A complete prescribing conversation for a woman of reproductive age covers three items: fertility may return during treatment even after years of irregular cycles; contraception should not rely on cycle tracking while cycles are changing, and oral contraceptives need a backup method on tirzepatide; and a planned pregnancy should trigger a preconception visit, a stop date for the drug, and folate in advance.

Interpretation

Restored fertility on GLP-1 therapy follows from the drug working as intended on the metabolic drivers of PCOS and obesity-related anovulation. The published data so far show low documented contraception use at the time of prescribing, a measurable pregnancy rate within six months, and no detected increase in harm from exposure around conception, with the caveat that all of it is observational and the labels still say to stop two months before trying.

Sources

Legro RS, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism, 2013;98(12):4565-4592. doi:10.1210/jc.2013-2350
Teede HJ, et al. Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Journal of Clinical Endocrinology and Metabolism, 2023;108(10):2447-2469. doi:10.1210/clinem/dgad463
Nylander M, Frøssing S, Clausen HV, Kistorp C, Faber J, Skouby SO. Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial. Reproductive BioMedicine Online, 2017;35(1):121-127. doi:10.1016/j.rbmo.2017.03.023
Zhou L, Qu H, Yang L, Shou L. Effects of GLP1RAs on pregnancy rate and menstrual cyclicity in women with polycystic ovary syndrome: a meta-analysis and systematic review. BMC Endocrine Disorders, 2023;23:245. doi:10.1186/s12902-023-01500-5
Fox News, April 16, 2024. "Ozempic babies: Women claim weight-loss drugs are making them more fertile and experts agree." https://www.foxnews.com/health/ozempic-babies-women-claim-weight-loss-drugs-fertile-experts-agree. Healthline, "Ozempic babies: unplanned pregnancies." https://www.healthline.com/health-news/ozempic-babies-unplanned-pregnancies
Thapaliya et al. Incidence of GLP-1 receptor agonist use by women of reproductive age attending general practices in Australia, 2011-2022. Medical Journal of Australia, 2025. doi:10.5694/mja2.70026
D'Antonio F, et al. GLP-1 receptor agonist exposure in the periconceptional period and adverse obstetric outcomes: a systematic review and meta-analysis. Med, 2026. doi:10.1016/j.medj.2026.101267
Huybrechts KF, et al. Target trial emulation of GLP-1 receptor agonist continuation into the first trimester, US insurance claims 2011 to 2024. Annals of Internal Medicine, 2026. doi:10.7326/ANNALS-25-04820 (title paraphrased and author order to be confirmed against the journal record)
Naderpoor N, et al. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Human Reproduction Update, 2015;21(5):560-574. doi:10.1093/humupd/dmv025
Ozempic (semaglutide) injection, US prescribing information, Novo Nordisk, section 8.3: discontinue at least 2 months before a planned pregnancy. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf
Wegovy (semaglutide) injection, US prescribing information, Novo Nordisk, section 8.3: discontinue at least 2 months before a planned pregnancy because of the long half-life of semaglutide.
Eli Lilly Medical Information. Can adults with obesity or overweight taking Zepbound also take oral contraceptives? https://medical.lilly.com/us/products/answers/can-adults-with-obesity-or-overweight-taking-zepbound-also-take-oral-contraceptives-211019
Centers for Disease Control and Prevention. Folic acid: key findings, are women getting enough folic acid? (neural tube defects occur in the first month of pregnancy). https://www.cdc.gov/ncbddd/folicacid/features/kf-women-enough-folic-acid.html. Review article, PubMed Central: neural tube closure is usually complete by 28 days post-conception. https://pmc.ncbi.nlm.nih.gov/articles/PMC3137839
Centers for Disease Control and Prevention. CDC's work to understand and prevent neural tube defects: 400 mcg folic acid daily for women aged 15 to 45, starting at least one month before pregnancy. https://www.cdc.gov/NCBDDD/folicacid/aboutus.html
MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. The Lancet, 1991;338(8760):131-137. PMID 1677062. https://pubmed.ncbi.nlm.nih.gov/1677062/

Female sexual dysfunction: common, undercounted, and rarely one problem

2026-11-11T00:00:00Z

How common sexual dysfunction is in women depends on one methodological choice: whether distress is required for the diagnosis. A 2025 cross-sectional study of 5,468 Australian women aged 40 to 69, published in The Lancet Obstetrics, Gynaecology & Women's Health, found that about one in four met criteria for a sexual dysfunction when distress was required, and another one in four had sexually related distress without an identified dysfunction [1]. Low desire was reported by 13.3 percent, impaired arousal by 13.1 percent, and poor sexual self-image by 12.8 percent [1]. Meta-analyses that pool questionnaire scores, most of them with no distress requirement, report higher figures: a 2026 meta-analysis of 23 studies and 11,892 postmenopausal women put sexual dysfunction at 61 percent [2]. Both numbers are informative. Roughly one in four midlife women has a sexual problem that bothers her; a majority of postmenopausal women score in the dysfunction range on a questionnaire.

Desire is not a lab value

Low desire is the problem women report most often. In PRESIDE, a 2008 US survey of 31,581 women, 38.7 percent reported low desire, 43.1 percent reported any sexual problem, and 22.2 percent reported distress about one [3]. It is also hard to pin to a single cause. The 2024 New England Journal of Medicine review by Davis frames the problem as multifactorial, with biological, psychological, and social contributors, and treats assessment as the first step [4]. In practice that assessment covers depression and its treatments (SSRIs and SNRIs are frequent contributors), relationship context, stress and sleep, pain with intercourse, and genitourinary syndrome of menopause, and each has its own treatment. Hypoactive sexual desire disorder, low desire with distress and no better explanation, affected about 10 percent of women in PRESIDE [3]. It is a diagnosis reached after the other causes are addressed, not before.

The tissue problem underneath many cases

Genitourinary syndrome of menopause is common. The 2020 Menopause Society position statement cites a range of 27 to 84 percent of postmenopausal women, depending on the survey, and calls the condition underdiagnosed and undertreated [5]. The symptoms are dryness, burning, pain with sex, urinary urgency, and recurrent urinary infections, driven by estrogen loss in genital tissue. Unlike hot flashes, it tends not to resolve on its own.

The 2025 AUA/SUFU/AUGS guideline (Kaufman et al.) gives a strong recommendation to offer low-dose vaginal estrogen for vulvovaginal dryness, irritation, and pain with sex, and a moderate recommendation to use it to reduce recurrent urinary tract infections [6]. The infection effect was first shown in a 1993 randomized trial of intravaginal estriol in 93 postmenopausal women, in which infections fell from 5.9 to 0.5 per patient-year [7]. A 2008 Cochrane review found that vaginal estrogen reduced recurrent infections in both placebo-controlled trials it identified, with the size of the effect depending on the product and duration (relative risks 0.25 and 0.64), while oral estrogen did not [8]. Vaginal DHEA and the oral drug ospemifene are alternatives [5, 6]. Energy-based treatments marketed for the same symptoms, principally vaginal laser, are not supported by the 2025 guideline [6]. In a 2021 sham-controlled trial of 85 women published in JAMA, fractional CO2 laser did no better than sham at 12 months on symptom severity, quality of life, or vaginal histology [9].

Pain deserves separate emphasis because it reorganizes everything downstream: a woman who expects pain loses desire, and desire-directed treatment fails until the pain is found and treated. The cause may be tissue change, infection, skin disease such as lichen sclerosus, or an overactive pelvic floor. In that last case the usual advice to do Kegels may not help, and the muscles need assessment by a pelvic floor physiotherapist before any exercise program is chosen [10].

Interpretation

The evidence supports a sequence: treat pain first, then tissue, then review medications and mood, and only then consider desire-specific therapy. In the Australian data, about half of midlife women reported poor sexual wellbeing [1], and the Davis review notes that fewer than half of women with sexual dysfunction seek medical help [4].

Sources

Wang, Islam, Bond, Skiba, Davis SR. Sexual dysfunction in women at midlife: a cross-sectional study of data from the Australian Women's Midlife Years study. The Lancet Obstetrics, Gynaecology & Women's Health, 2025. doi:10.1016/j.lanogw.2025.100024
Rodríguez-García M, Fagundo-Rivera J, Gómez-Salgado J, Partida-Márquez AL. Female sexual dysfunction in postmenopausal women: a systematic review and meta-analysis. Sexuality Research and Social Policy, 2026. doi:10.1007/s13178-026-01289-7
Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: prevalence and correlates. Obstetrics & Gynecology, 2008;112(5):970-978. PMID 18978095.
Davis SR. Sexual dysfunction in women. New England Journal of Medicine, 2024;391(8):736-745. doi:10.1056/NEJMcp2313307
Faubion SS, et al. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause, 2020;27(9):976-992. doi:10.1097/GME.0000000000001609
Kaufman MR, Ackerman LA, Amin KA, et al. The AUA/SUFU/AUGS guideline on genitourinary syndrome of menopause. Journal of Urology, 2025;214(3):242-250. doi:10.1097/JU.0000000000004589
Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. New England Journal of Medicine, 1993;329(11):753-756. PMID 8350884.
Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database of Systematic Reviews, 2008;(2):CD005131. doi:10.1002/14651858.CD005131.pub2
Li FG, et al. Effect of fractional carbon dioxide laser vs sham treatment on symptom severity in women with postmenopausal vaginal symptoms: a randomized clinical trial. JAMA, 2021;326(14):1381-1389. doi:10.1001/jama.2021.14892
Padoa A, McLean L, Morin M, et al. The overactive pelvic floor (OPF) and sexual dysfunction. Part 2: evaluation and treatment of sexual dysfunction in OPF patients. Sexual Medicine, 2021;9(1):76-92.

Testosterone therapy for women: one supported indication, and prescribing that has outgrown it

2026-11-12T00:00:00Z

No testosterone product is FDA-approved for women in the United States. Approved testosterone products exist only for men with low testosterone and an associated medical condition [1]. Every prescription a woman receives is off-label, typically a fraction of a male dose or a compounded preparation, and use is expanding. An analysis of Epic Cosmos electronic health records found the testosterone prescribing rate among eligible US women rose from 50.0 to 130.8 per 100,000 between 2016 and 2025, about 2.6-fold, with a 32 percent annual increase from 2022 to 2025. By 2025 that was 90,482 prescriptions, up 59 percent from 2024. Recorded reasons were led by menopausal symptoms (35 percent), decreased libido (24 percent), and hormone replacement (17 percent). Hypoactive sexual desire disorder, the one indication the trial evidence supports, accounted for about 8 percent [2].

What the trials show

The evidence base is a 2019 systematic review and meta-analysis in The Lancet Diabetes and Endocrinology that pooled 46 reports from 36 randomized trials and 8,480 women [3]. In postmenopausal women, testosterone improved sexual desire, arousal, orgasm, pleasure, and self-image, reduced sexual distress, and increased satisfying sexual events by a mean difference of 0.85 per month. That is roughly one additional satisfying event a month. Only three trials with 226 premenopausal women were available, so the authors drew no conclusions for that group. The review found no benefit for cognition, bone density, body composition, or muscle strength, with the caveat that few women contributed data on those outcomes [3].

The 2019 Global Consensus Position Statement, written by Davis and colleagues and endorsed by the Endocrine Society, the International Menopause Society, the North American Menopause Society, the International Society for Sexual Medicine, the International Society for the Study of Women's Sexual Health, the European Menopause and Andropause Society, the Royal College of Obstetricians and Gynaecologists, and other societies, recognizes one evidence-based indication: hypoactive sexual desire disorder in postmenopausal women, after other contributing causes have been evaluated. It found insufficient evidence to support testosterone for cognition, bone health, general wellbeing, or depression, recommends doses that keep blood levels in the physiologic premenopausal range, and recommends against supraphysiologic dosing and against compounded testosterone [4].

There is no diagnosable testosterone deficiency in women. The Endocrine Society's 2014 guideline advises against making a diagnosis of androgen deficiency in healthy women because no defined syndrome exists and no data link blood levels to specific symptoms; baseline testosterone did not predict who responded to treatment [5]. Blood levels are therefore used to confirm the dose is not supraphysiologic, not to decide who should be treated. The guideline suggests checking levels every six months during treatment and stopping in women who have not responded by six months [5].

Dose and form decide the side effects

Trial dosing was transdermal, by patch, gel, or cream, and aimed at the normal premenopausal range [3, 4]. At those doses the recorded costs were more acne, more hair growth, and a small increase in weight; no serious adverse events were reported [3]. Route mattered for lipids. Oral testosterone raised LDL cholesterol and lowered HDL cholesterol, while non-oral routes did not, which is why the authors preferred patches and creams [3].

Injections and pellets, common in cash-pay practice, were not the formulations studied in these trials. Pellets are usually compounded, cannot be removed or adjusted once implanted, and a 2025 review of compounded hormonal pellets found no peer-reviewed studies showing they are safer or more effective than approved products; it estimated pellets account for 10 to 15 percent of testosterone prescriptions for US women [6]. Compounded products also add a potency variable. In FDA surveys of compounded drugs that included female hormone products, 34 percent of sampled products failed quality testing in 2001 and 33 percent failed in 2006, with measured potency in the 2006 sample ranging from 67.5 to 268.4 percent of the labeled amount [7, 8]. Those surveys were small and did not test testosterone pellets specifically.

The unresolved safety question

The trials were short. The consensus statement and the 2014 guideline both note that safety data for testosterone in women do not extend beyond 24 months, that the trials were too small to assess breast cancer risk, and that women at elevated cardiometabolic risk were generally excluded [4, 5]. No trial has been powered for cardiovascular or breast outcomes.

On September 17, 2026, the FDA's Office of Women's Health and Center for Drug Evaluation and Research held a public workshop, "Testosterone Use in Menopausal Women," to review the evidence and knowledge gaps and to inform future research and drug development [9]. Dr. Christina Chang, division director in CDER's urology, obstetrics and gynecology division, said the agency is aware of increasing off-label use and that no approved indication exists for menopausal women. Specialists at the meeting said questions about long-term safety remain unanswered and that many women seek testosterone for energy and mood, uses no guideline supports [10]. The public docket (FDA-2026-N-5479) closed October 19, 2026 [9]. As of this writing the FDA has announced no decision. Regulators want long-term outcome data, no sponsor has funded that trial, and off-label prescribing has filled the space in the meantime.

Where this leaves a patient

For a postmenopausal woman with distressing low desire and other causes addressed, transdermal testosterone at a physiologic dose is an evidence-based option with an expected benefit of about one additional satisfying sexual event per month, reassessed at three to six months and stopped if nothing has changed [3, 4, 5]. For energy, mood, cognition, muscle, bone, or aging, no randomized trial shows benefit, and the formulations sold most heavily for those uses, pellets and injections, are the ones with the least trial data behind them [3, 4, 6].

Sources

US Food and Drug Administration. Testosterone Information. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/testosterone-information
Avivi I, Stuenkel C, Sampath-Kumar R, et al. Accelerating Testosterone Prescribing for U.S. Women: Implications for Cardiovascular Safety. JACC: Advances. Published online May 13, 2026. doi:10.1016/j.jacadv.2026.102724
Islam RM, Bell RJ, Green S, Page MJ, Davis SR. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. The Lancet Diabetes and Endocrinology. 2019;7(10):754-766. https://pubmed.ncbi.nlm.nih.gov/31353194/
Davis SR, Baber R, Panay N, et al. Global Consensus Position Statement on the Use of Testosterone Therapy for Women. Journal of Clinical Endocrinology and Metabolism. 2019;104(10):4660-4666. https://pmc.ncbi.nlm.nih.gov/articles/PMC6821450/
Wierman ME, Arlt W, Basson R, et al. Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism. 2014;99(10):3489-3510. https://www.endocrine.org/clinical-practice-guidelines/androgen-therapy-in-women
Compounded hormonal pellets: a critical review of current evidence and risks. 2025. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341420/
US Food and Drug Administration. Report: Limited FDA Survey of Compounded Drug Products (2001). Archived at https://webharvest.gov/peth04/20041112082657/http:/www.fda.gov/cder/pharmcomp/survey.htm
US Food and Drug Administration. 2006 Limited FDA Survey of Compounded Drug Products. Archived at https://webarchive.library.unt.edu/eot2008/20090511183313/http:/www.fda.gov/cder/pharmcomp/survey_2006.htm
US Food and Drug Administration. FDA Public Meeting: Testosterone Use in Menopausal Women, September 17, 2026. https://www.fda.gov/consumers/womens-health-events/fda-public-meeting-testosterone-use-menopausal-women-09172026 ; Federal Register notice, August 18, 2026, Docket FDA-2026-N-5479. https://www.federalregister.gov/documents/2026/08/18/2026-16829/testosterone-use-in-menopausal-women-public-workshop-request-for-comments
ABC News. FDA examines use of testosterone prescriptions for menopause. September 18, 2026. https://abcnews.com/Health/fda-examines-testosterone-prescriptions-menopause/story?id=136570571

Menopausal hormone therapy after the WHI: what the follow-up data changed

2026-11-13T00:00:00Z

In July 2002, the Women's Health Initiative reported that combined estrogen plus progestin increased the risks of breast cancer, coronary events, stroke, and blood clots, and the trial arm was stopped early, after a mean of 5.2 years of follow-up [1]. Prescribing fell sharply worldwide within a year. Two decades of follow-up analysis have produced a more detailed picture, and the difference between the 2002 headline and the current reading comes down to who was studied and what they were given.

What the original trial tested

The WHI estrogen plus progestin trial randomized 16,608 postmenopausal women with a uterus to one regimen, oral conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg daily, or placebo. Mean age at enrollment was 63.3 years; about two-thirds of participants were over 60, and only about 11 percent were aged 50 to 54 [1]. The reported hazard ratios were 1.29 for coronary heart disease, 1.26 for invasive breast cancer, 1.41 for stroke, and 2.13 for pulmonary embolism, with the breast cancer interval reaching 1.00 and the coronary interval crossing 1 after adjustment for multiple comparisons [1]. These were relative increases applied to low absolute rates in that age group. The trial was designed as a chronic disease prevention study in older women, not a study of symptom treatment in women around 50. Its results were applied to both, and prescribing guidance for younger women was rewritten on data from older ones.

What later analysis added

Age and timing. The 2013 WHI report of 13 years of cumulative follow-up found that outcomes differed by age [2]. In the estrogen-alone trial, women aged 50 to 59 had a hazard ratio for coronary heart disease of 0.63 (95% CI 0.36 to 1.08) and a trend toward lower all-cause mortality, while women 60 and older showed no difference from placebo [2]. The 2017 WHI mortality analysis, covering 27,347 women across both trials over 18 years, found no overall difference in all-cause, cardiovascular, or cancer mortality with hormone therapy (HR 0.99, 95% CI 0.94 to 1.03); among women aged 50 to 59 during the intervention phase, all-cause mortality was lower with hormone therapy (HR 0.69, 95% CI 0.51 to 0.94), a pattern not seen in the older age groups [3]. This age-dependent pattern is what is usually meant by the timing hypothesis. The WHI investigators describe it as a trend consistent with the hypothesis, not proof of it, and they continue to state that the findings do not support hormone therapy for chronic disease prevention [2, 3].

Estrogen alone, in women who had a hysterectomy, did not increase breast cancer. During the intervention phase the hazard ratio was 0.79, and over 13 years of cumulative follow-up breast cancer incidence was significantly reduced in the estrogen-alone group [2]. The increase in breast cancer appeared in the combined regimen, which used medroxyprogesterone acetate. The WHI did not test other progestogens, so it cannot say whether a different progestogen would have produced a different result.

Route of administration. Oral estrogen passes through the liver before reaching the circulation, where it increases production of clotting factors. In the French ESTHER case-control study of 271 women with a first idiopathic venous thromboembolism and 610 matched controls, current oral estrogen use was associated with an odds ratio of 4.2 (95% CI 1.5 to 11.6) compared with nonusers, while transdermal estrogen was associated with an odds ratio of 0.9 (95% CI 0.4 to 2.1) [4]. A 2008 meta-analysis of eight observational studies and nine randomized trials by the same group found an odds ratio of 2.5 (95% CI 1.9 to 3.4) for oral estrogen and 1.2 (95% CI 0.9 to 1.7) for transdermal estrogen, with oral risk highest in the first year of use [5]. The transdermal finding rests on observational data; no randomized trial has tested transdermal estrogen against oral for venous thromboembolism [5]. Transdermal estradiol and oral micronized progesterone are chemically identical to the hormones the ovary makes, and neither was the regimen the WHI tested.

What progesterone is for. A woman with a uterus who takes systemic estrogen needs a progestogen to protect the uterine lining, because unopposed estrogen raises the risk of endometrial hyperplasia and cancer [6]. The FDA kept this risk in the boxed warning for systemic estrogen-alone products when it removed the other warnings in 2025 and 2026 [11, 12]. Micronized progesterone fills the protective role and has a measurable effect on sleep: in a crossover trial of 10 healthy postmenopausal women, 300 mg of oral micronized progesterone at night reduced time awake on sleep EEG from about 80 to about 54 minutes without impairing daytime cognition [7], and a 2021 meta-analysis of randomized trials found micronized progesterone shortened sleep onset latency, with inconsistent results for total sleep time and sleep efficiency and clearer effects at 200 to 300 mg than at 100 mg [8]. A levonorgestrel intrauterine device delivers progestogen to the lining with little systemic exposure. A 2011 meta-analysis of six randomized trials (518 women) found rates of proliferative endometrium with the device comparable to systemic progestogens, though the longest trial ran 24 months [9]. In the United States this use is off-label, and only 3 of 72 trials of endometrial protection reviewed at the 2025 Menopause Society meeting studied the hormonal IUD [10].

What the FDA changed

On November 10, 2025, HHS and the FDA announced that the boxed warning on menopausal hormone therapy, added in 2003 on the basis of the WHI, would lose its language on cardiovascular disease, breast cancer, and probable dementia, following a literature review, a July 2025 expert panel, and a public comment period; the endometrial cancer warning stays on systemic estrogen-alone products, and cardiovascular and breast cancer information remains elsewhere in the labeling [11]. On February 12, 2026, the FDA approved the first revised labels for six products (Prometrium, Divigel, Cenestin, Enjuvia, Estring, and Bijuva), with submissions from 29 manufacturers under review [12]. Critics, including Public Citizen's Worst Pills, Best Pills, argued the change rested on reinterpretation of existing data, not new safety data [11].

Where this leaves current practice

The WHI answered a narrow question: oral conjugated estrogen plus medroxyprogesterone, started at a mean age of 63, caused more harm than benefit as a prevention strategy. It did not test transdermal estradiol, micronized progesterone, or treatment started near menopause for symptoms. The 2022 Menopause Society position statement endorses hormone therapy for vasomotor symptoms and the genitourinary syndrome of menopause, notes that it prevents bone loss and fracture, and frames the decision around age, time since menopause, and individual risk, with periodic reassessment [6]. The follow-up data support that framing. They do not show that hormone therapy prevents chronic disease, and the WHI investigators still say so [2, 3].

Sources

Writing Group for the Women's Health Initiative Investigators (Rossouw JE, et al.). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333. https://jhanley.biostat.mcgill.ca/c609/material/hrtJama2002.pdf
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368. doi:10.1001/jama.2013.278040
Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women's Health Initiative randomized trials. JAMA. 2017;318(10):927-938. https://menopause.org.au/hp/studies-published/menopausal-hormone-therapy-and-long-term-all-cause-and-cause-specific-mortality-the-whi-randomized-trials
Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115(7):840-845. https://pubmed.ncbi.nlm.nih.gov/17309934/
Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336(7655):1227-1231. https://www.bmj.com/content/336/7655/1227
The North American Menopause Society Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794. doi:10.1097/GME.0000000000002028. https://www.menopause.org/docs/default-source/professional/nams-2022-hormone-therapy-position-statement.pdf
Schüssler P, et al. Progesterone reduces wakefulness in sleep EEG and has no effect on cognition in healthy postmenopausal women. Psychoneuroendocrinology. 2008;33(8):1124-1131. https://pubmed.ncbi.nlm.nih.gov/18676087/
Nolan BJ, Liang B, Cheung AS. Efficacy of micronized progesterone for sleep: a systematic review and meta-analysis of randomized controlled trial data. Journal of Clinical Endocrinology and Metabolism. 2021;106(4):942-951. doi:10.1210/clinem/dgaa873
Somboonporn W, et al. Levonorgestrel intrauterine system versus systemic progestogens for endometrial protection in women using estrogen therapy: meta-analysis of randomized trials. Menopause. 2011. (Six trials, 518 participants.)
Contemporary OB/GYN. Michelle Wise, MD, discusses levonorgestrel IUD offering effective endometrial protection during hormone therapy. October 23, 2025. https://www.contemporaryobgyn.net/view/michelle-wise-md-discusses-levonorgestrel-iud-offering-effective-endometrial-protection-during-hormone-therapy
US Department of Health and Human Services and US Food and Drug Administration. HHS Advances Women's Health, Removes Misleading FDA Warnings on Hormone Replacement Therapy. Press announcement, November 10, 2025. https://www.fda.gov/news-events/press-announcements/hhs-advances-womens-health-removes-misleading-fda-warnings-hormone-replacement-therapy-0 ; critique: Worst Pills, Best Pills, https://www.worstpills.org/newsletters/view/1700
US Food and Drug Administration. FDA Approves Labeling Changes to Menopausal Hormone Therapy Products. Press announcement, February 12, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-labeling-changes-menopausal-hormone-therapy-products