Does the Risk Outweigh the Benefit?

Click to Enlarge: Source: European Urology

WASHINGTON — Beyond the political fight over the DoD’s new testosterone screening mandate remains a clinical question: Does population-level screening of a mostly asymptomatic, young military population offer significant benefit or simply raise risk?

The memorandum directing the policy makes testosterone screening a mandatory element of the Periodic Health Assessment for active-duty and reserve personnel 30 and older, with screening optional for younger service members.

The memo’s clinical rationale leans heavily on “operator syndrome,” which refers to a constellation of issues tied in a 2020 study to the extreme physical and psychological demands characteristic of special operations careers, including chronic combat stress, repeated blast wave exposures, traumatic brain injuries, and chronic sleep deprivation.1

While often associated with a sharp drop in testosterone, operator syndrome is a complex pattern of health concerns including traumatic brain injury (TBI), sleep issues, obstructive sleep apnea, orthopedic problems, vestibular and vision impairments, headaches, and sexual health issues. It also captures a pattern of mental and social health concerns such as cognitive impairment, memory and concentration difficulties, substance abuse, depression, suicide, anger, anxiety, hyper vigilance, stress reactivity, and difficulty with the transition to civilian life as well as marital, family, and community dysfunction.

Given the range of symptoms and number of body systems affected, a holistic approach to affected individuals is recommended, starting with good nutrition, adequate sleep, treatment of diabetes and obesity, and stress management techniques. The original study on operator syndrome called for integrated neurological, medical, sleep, pain, psychiatric, genetic, microbiota, and metabolic assessment and treatment, and viewed low testosterone as a consequence of the rigors of SOF training and careers, not a cause of the syndrome itself.

There also remains a question of efficacy. A study of 50 men that tested supplemental testosterone (200 mg/wk) in short-term energy deficit conditions found that the therapy increased lean body mass but did not reduce lower-body muscle performance decline or improve health-related biomarkers.2 In addition, a small study of special operations forces (SOF) members who had experienced mild to moderate TBI concluded that “these findings indicate testosterone use may not significantly affect symptoms of chronic pain, chronic headache, insomnia, PTSD, anxiety, and depression.” The only difference found between those treated with testosterone and those who were not was a higher pain score in individuals receiving hormone therapy.3

An Ongoing Debate

Click to Enlarge: Image explaining the contraceptive effect of exogenous testosterone. In summary, it works by 2 mechanisms, decreasing intra-testicular testosterone, and inhibiting spermatogenesis. Most of the intra-testicular testosterone is made by the Leydig Cells in the testis. When exogenous testosterone is present, it inhibits gonadotropin-releasing hormone (GnRH) production which in turn inhibits luteinizing hormone (LH) production and decreases endogenous testosterone production by the Leydig cells, decreasing the intra-testicular testosterone concentration. Inhibiting GnRH production also inhibits follicle stimulating hormone (FSH) release, which impairs spermatogenesis in the Sertoli cells. Source: The World Journal of Men’s Health

The debate over testosterone predates the operator syndrome discussion by decades, however, and has focused primarily on safety.

Charles Huggins, MD, made his Nobel Prize-winning discovery that androgen deprivation shrank prostate cancer tumors in 1941.4 His seminal work included a conclusion based on one patient, that the converse was also true—testosterone supplementation stimulates prostate cancer.

A meta-analysis of studies from 1941 to 2008 found that the connection between exogenous testosterone and prostate cancer was far from linear, and that above the near-castrate range, there was little connection.5 (Another analysis in 2024 extended the findings, concluding that there was insufficient evidence of risk for increasing the aggressiveness of prostate cancer in men managed with active surveillance.)6

“Low-T” clinics rapidly multiplied, but new concerns emerged. Researchers prematurely discontinued a 2010 study in 209 older men because of elevated risk in a six-month period: 23 subjects in the testosterone group vs. five in the placebo group experienced cardiovascular-related adverse events. In 2013, a landmark VA study published in JAMA that enrolled 8,709 veterans, showed that hypogonadal men undergoing testosterone therapy had a 29% greater risk of death, heart attack, or stroke than those not on the hormone over an average follow-up period of 27.5 months.7 In both studies, the participants had a high rate of cardiovascular disease at initiation.

The FDA required testosterone products to carry warnings of cardiovascular risk in 2015.

In 2023, the industry-sponsored TRAVERSE trial in 5,246 men with hypogonadism and at risk for or with existing CVD challenged the findings from a decade earlier, showing no increase in cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or coronary revascularization with 33 months of follow up.8 A companion analysis of the same trial found roughly a 50% relative increase in pulmonary embolism and a higher fracture incidence among men on testosterone.

What the Guidelines Say

With that mixed background and the DoD mandate in mind, The Endocrine Society restated its clinical practice guidelines in July. Notably, the society maintained a conservative posture, saying, “there is insufficient evidence to support a general recommendation to perform population-level screening for hypogonadism in asymptomatic men with measurement of blood testosterone level.”

Diagnosing hypogonadism requires both symptoms of low testosterone and consistently low levels on accurately measured blood tests. Symptoms alone, the society notes, are also not diagnostic, as low energy, libido and mood have many causes in aging men, and reversible contributors such as obesity, corticosteroids, obstructive sleep apnea or opioid use need to be ruled out first.9

Testing accuracy compounds the diagnostic problem, the Society adds. Not all testosterone assays are standardized, so the same blood sample can read as low or normal depending on the lab and method used. The CDC’s Hormone Standardization (HoST) program was created to close this gap by certifying qualifying assays as harmonized.

Jason Goldman, MD, internal medicine physician and immediate past president of the American College of Physicians, put the frequent discordance between initial testing and diagnosis in concrete terms: up to 40% of men tested in one study had low readings, but fewer than 2% had any accompanying symptoms.10

Weighing Benefit Against Risk

The Endocrine Society considers the long-term prostate cancer risk unresolved, as it argues that trials have not followed patients long enough to detect it.11

Goldman said the new policy increases known risks. “Testosterone therapy can increase heart attack risk, thicken the blood, cause blood clots, worsen sleep apnea, cause weight gain, cause infertility, make people more aggressive, [and] can make prostate cancer worse,” Goldman said. “Just giving testosterone is not going to optimize troops but could cause severe harm. This is not good, sound medical strategy.”

Jeremy Samuel Faust, MD, emergency physician, Brigham and Women’s Hospital, assistant professor, Harvard Medical School, and editor-in-chief of MedPage raised another safety concern, with specific importance to a military population. “In the big trials, people at higher risk of suicide were excluded from the testosterone trials because of that fear,” Faust said. “I worry about that, and I think it’s really important that we keep our people safe.”12 He added that men with low testosterone but no symptoms “do not benefit from supplementation,” further weakening the case for screening asymptomatic servicemembers.

Beyond Debate

While the effect of testosterone therapy on CVD and cancer may remain unresolved, its impact on fertility is uncontroversial. Testosterone suppresses luteinizing hormone/follicle-stimulating hormone, which is absolutely critical for sperm development. Two World Health Organization studies found that testosterone supplementation for six months resulted in no measurable sperm in 65% to 98% of men.13 After discontinuation of testosterone therapy, about 65% of men recover to 20 million sperm/mL at six months and 100% at two years, though duration of treatment and age may make recovery more difficult.14 For young men at peak family formation age, impaired fertility represents a significant downside.

A separate strand of research complicates the picture further. A meta-analysis of 12 studies including more than 102,000 men presented July 7 at the European Society of Human Reproduction and Embryology found that total and free testosterone, along with sex hormone-binding globulin, have dropped significantly worldwide since 1972, with the rate of decline nearly doubling after 2000.15 Total testosterone plummeted 54%. Shifting population ranges raise questions about what counts as a normal testosterone level and treatment becomes more complex when “rising rates of obesity and metabolic disorders, exposure to endocrine-disrupting chemicals like phthalates or microplastics, sedentary lifestyles, unhealthy dietary patterns, and chronic psychosocial stress have all been implicated”16 in the decline.

None of this forecloses testosterone therapy for troops who are appropriately diagnosed. The Endocrine Society and the trial data agree that men with confirmed hypogonadism from a disease of the testes, pituitary or hypothalamus benefit from treatment at appropriate physiologic doses. The clinical debate now centers on whether mandating screening across a young, mostly asymptomatic population, using assays that are often not standardized, and without a clear protocol for what happens after a low reading, does more long-term harm than good.

 

  1. Frueh BC, Madan A, Fowler JC, et al. “Operator syndrome”: a unique constellation of medical and behavioral health-care needs of military special operation forces. Int J Psychiatry Med. 2020;55(4):281-295.
  2. Pasiakos SM, Berryman CE, Karl JP, et al. Effects of testosterone supplementation on body composition and lower-body muscle function during severe exercise- and diet-induced energy deficit: A proof-of-concept, single centre, randomised, double-blind, controlled trial. EBioMedicine. 2019 Aug;46:411-422. doi: 10.1016/j.ebiom.2019.07.059. Epub 2019 Jul 27. PMID: 31358477; PMCID: PMC6711889.
  3. Barnett N, Ljubic M, Chung J, Capizzi A. Testosterone and neurobehavioral outcomes in special operations forces military with multiple mild traumatic brain injury. NeuroRehabilitation. 2024;55(3):271-279. doi: 10.3233/NRE-230291. PMID: 38995807; PMCID: PMC11612980.
  4. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer research. 1941 Apr 1;1(4):293-7.
  5. Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009 Feb;55(2):310-20. doi: 10.1016/j.eururo.2008.09.024. Epub 2008 Sep 24. PMID: 18838208.
  6. Kaplan-Marans E, Zhang TR, Hu JC. Oncologic Outcomes of Testosterone Therapy for Men on Active Surveillance for Prostate Cancer: A Population-based Analysis. Eur Urol Open Sci. 2024 Jan 31;60:36-43. doi: 10.1016/j.euros.2024.01.005. PMID: 38375342; PMCID: PMC10874869.
  7. Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013 Nov 6;310(17):1829-36. doi: 10.1001/jama.2013.280386. Erratum in: JAMA. 2014 Mar 5;311(9):967. PMID: 24193080.
  8. Lincoff AM, Bhasin S, Flevaris P, et al; TRAVERSE Study Investigators. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023 Jul 13;389(2):107-117. doi: 10.1056/NEJMoa2215025. Epub 2023 Jun 16. PMID: 37326322.
  9. Endocrine Society. Statement on Testosterone Replacement Therapy. Washington, DC: Endocrine Society; 2026 Jul 16.
  10. Goldman J. LinkedIn. July 16, 2026.
  11. Snyder PJ, Bauer DC, Ellenberg SS, et al. Testosterone treatment and fractures in men with hypogonadism. N Engl J Med. 2024;390(3):203-211.
  12. Faust JS. “The Arena.” CNN. July 16, 2026.
  13. Patel AS, Leong JY, Ramos L, Ramasamy R. Testosterone Is a Contraceptive and Should Not Be Used in Men Who Desire Fertility. World J Mens Health. 2019 Jan;37(1):45-54. doi: 10.5534/wjmh.180036. Epub 2018 Oct 10. PMID: 30350483; PMCID: PMC6305868.
  14. Stahl PJ. Recovery of spermatogenesis after hormone therapy: what to expect and when to expect it. Fertil Steril. 2017 Feb;107(2):338-339. doi: 10.1016/j.fertnstert.2016.11.033. PMID: 28160921.
  15. Levy A, Hansen LS, Abu Ahmad W, et al. Temporal trends in total and free testosterone (1972-2019): a systematic review and meta-trend analysis. Hum Reprod. 2026;41(Suppl 1):deag083.202.
  16. Fraile-Martínez Ó, Ortega MA, García-Montero C. Understanding the Secular Decline in Testosterone: Mechanisms, Consequences, and Clinical Perspectives. Int J Mol Sci. 2026 Jan 9;27(2):692. doi: 10.3390/ijms27020692. PMID: 41596342; PMCID: PMC12841019.