Testosterone Replacement Therapy Takes More Than A Blood Test...

 

Organization (Year)	Testing Requirement	Diagnostic Threshold and Notes
Endocrine Society (2018)	Fasting total testosterone measured on 2 separate mornings, both unequivocally low, plus consistent symptoms or signs	Lower limit 264 ng/dL (CDC-standardized assays). Measure free testosterone if SHBG may be altered (obesity, diabetes) or total testosterone is borderline
American Urological Association (2018)	Total testosterone measured on 2 separate early mornings, both low (Strong Recommendation, Grade A)	Consistently <300 ng/dL. Ideally the same lab and method for both samples
Society for Endocrinology and Association for Clinical Biochemistry and Laboratory Medicine, UK (2024)	Total testosterone measured on 2 consecutive fasting mornings, both low	Action threshold <8 nmol/L (~230 ng/dL). 8–12 nmol/L is a gray zone that needs careful clinical correlation
References:   1:  Sargis RM, Davis AM. Evaluation and Treatment of Male Hypogonadism. JAMA. 2018;319(13):1375–1376. doi:10.1001/jama.2018.3182 2:  Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 May 1;103(5):1715-1744. doi: 10.1210/jc.2018-00229. PMID: 29562364. 3:  Mulhall JP, Trost LW, Brannigan RE, Kurtz EG, Redmon JB, Chiles KA, Lightner DJ, Miner MM, Murad MH,       Nelson CJ, Platz EA, Ramanathan LV, Lewis RW. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018 Aug;200(2):423-432. doi: 10.1016/j.juro.2018.03.115. Epub 2018 Mar 28. PMID: 29601923. 4:  Zucker IJ, Masterson TA. Comparison of American Urological Association and Endocrine Society guidelines on testosterone replacement. Int J Impot Res. 2022 Nov;34(7):626-629. doi: 10.1038/s41443-021-00477-w. Epub 2021 Oct 18. PMID: 34663926. 5:  Jayasena CN, de Silva NL, O'Reilly MW, MacKenzie F, Marrington R, Jones H, Livingston M, Downie P, Hackett G, Ramachandran S, Tomlinson J, David J, Boot C, Patel M, Tarling J, Wu F, Quinton R. Standardising the biochemical confirmation of adult male hypogonadism: A joint position statement by the Society for Endocrinology and Association of Clinical Biochemistry and Laboratory Medicine. Clin Endocrinol (Oxf). 2024 Nov;101(5):531-534. doi: 10.1111/cen.14929. Epub 2023 Jul 1. PMID: 37393195.  (UK) 6:  Grossmann M, Jayasena CN, Anawalt BD. Approach to the Patient: The Evaluation and Management of Men ≥50 Years With Low Serum Testosterone Concentration. J Clin Endocrinol Metab. 2023 Aug 18;108(9):e871-e884. doi: 10.1210/clinem/dgad180. PMID: 36995891; PMCID: PMC10438885.

 

We are living in the age of testosterone – for the second or third time.  Some are taking it to caricature levels. I started writing about it on this blog 13 years ago – as a form of cheating in sports and health and wellness hype.  I have written about a study that carefully screened men for hypogonadism and demonstrated moderate benefit on sexual functioning and some benefit with mood and depressive symptoms but no effect on physical functioning or vitality.  Since then, testosterone prescribing has continued unabated and expanded with the growth of telemedicine and advertising to the target audience. As a psychiatrist working during that time, I saw men who were clearly taking supraphysiological doses of testosterone for the anabolic effects.  I did not have to speculate about that use when I saw men with obvious muscular hypertrophy who told me they were taking testosterone because they liked the interpersonal effects when people noticed they had muscle. 

 

The major guidelines for testosterone replacement therapy are produced in the above table. The indication for replacement is hypogonadism by clinical evaluation and laboratory determination.  The laboratory guidelines vary slightly between organizations but they are generally consistent.  The current guideline in UpToDate uses a determination of two morning determinations of testosterone and a diagnosis of hypogonadism that considers the many causes of primary and secondary hyopgonadism.  The indications for therapy are more concrete than many medications that are purportedly overprescribed.  Cultural factors are more prominent than ever with the current administration mandating testosterone screening (2) for active and reserve military to optimize human performance and address Operator Syndrome.  Interestingly the Operator Syndrome is a collection of physical and psychological injuries – some of which may have been pre-existing conditions.  The endocrine aspect of this syndrome is secondary hypogonadism from blast injuries.  There is a significant differential diagnosis of both secondary and primary hypogonadism that include functional etiologies like acute and chronic illnesses, malnutrition, other endocrinopathies, various drugs, infections, and various toxins. The  value of including this as a feature of a non-specific syndrome seems questionable to me.  The best approach to this problem is a comprehensive assessment by an endocrinologist – not a testosterone level. 

 

What about the mass screening aspects?  The pie diagram is from the EMAS study (4) of 3,369 men ages 40-79.  The interesting finding is that only 2% of that population has symptomatic hypogonadism that would be treated with testosterone.  5% had low testosterone that normalized on repeat.  10% had persistently low testosterone but no symptoms of hypogonadism. 83% had normal testosterone on the first test.            

 

 

After the DOD release, Hennigar, et al did a retrospective study of pre-existing health data on military personnel with a focus on testosterone (5).  The analysis was based on a sample of 479 men with an average age 29.9 years.  Weighted mean morning total testosterone, sex hormone–binding globulin, and free testosterone concentrations were determined.  Using 2 cutoff levels of <300 ng/dL and < 264 ng/dL – weighted prevalences of the sample were calculated for < 30 yrs old and ≥ 30 yrs old.  A separate non-obese group was estimated using the 264 ng/dL cutoff.  Extrapolating those prevalence figures to the active-duty US Army personnel gives a range of 57,788 to 100,691 service men.  Using the EMAS study estimate for symptomatic hypogonadism that number is 7,862.

 

The authors of this study qualify their results by saying that this is only one morning fasting testosterone level. 30% of the low levels are expected to normalize on repeat, but that would still leave about 20% of this sample in the low range. The sample was not screened for specific symptoms of low testosterone or moderate to severe head injury that has been associated with blast injuries and post-traumatic hypopituitarism (7).  Obesity and body composition contributes and they note the normal weight cohort has a lower prevalence of low testosterone.  The stress of some military conditions can also suppress testosterone.  Army Ranger training can reversibly suppress testosterone levels by 50% (8).  That is attributed to energy deficit, sleep restriction, heavy physical work, and psychological stress effects on gonadotropin-releasing hormone and luteinizing hormone pulsatility.  This is a critical observation that appears to be omitted from both the formulation of Operator Syndrome and the rationale for screening.  Treatment in this case would be removal from the stressful military conditions rather than testosterone replacement.  It would also seem to be a factor in determining the optimal time and status for diagnosing post-traumatic hypopituitarism.

 

All the factors mentioned so far suggest that testosterone is over prescribed in the US population. Since the US has no comprehensive pharmacosurveillance indirect estimates are made using other samples. In 2013 an estimated 2.3M men were using testosterone.  That dropped to about 1.15M men after an FDA warning about cardiovascular effects (9). From 2018-2022 the number of men being treated increased 27% from 1.22M to 1.66M.  The data in that study was from 25 state prescription data monitoring programs (PDMPs).  Remaining states were prohibited from sharing that information and the authors suggest that more populous states need to be included (10).      

 

The current population of men between the ages of 40 and 79 is estimated to be about 72 million and they make up 21.5% of the total population. Using the EMAS estimate for true hypogonadism (low total and free testosterone and 3 sexual symptoms of 2.1% yields a total of 1.53M men with true hypogonadism.  That number is lower than the estimate of 1.66M  from 25 states (10).  In that study the fastest growing testosterone use groups were 35–44 (+58%) and 45–54 (+35%) – groups that according to the EMAS study have the lowest prevalence of hypogonadism.  This age mismatch combined with missing or normal baseline testosterone levels, non-specific symptoms (fatigue, low energy), and low treatment rates in the target population of men ≥ 60 with the highest rates of hypogonadism suggests overprescribing.

 

There is additional indirect evidence available.  Every viewing of streaming channels on the Internet generally produces an advertisement about the easy availability of testosterone prescriptions by telemedicine.  A recent secret shopper study (17, 18) of online platforms offering testosterone therapy found that none of the assessments were done by a physician and despite normal total and free testosterone levels and wanting to father a child - 7 of 8 platforms prescribed testosterone.  The associated commentary says this highlights a problem and this technique might be used by state medical boards.  An earlier study looked at the relationship between advertising and prescriptions and noted that each additional testosterone ad exposure was associated with 14 new tests, 5 new initiations, and 2 initiations without testing per million men. Unbranded "low T" ads had a stronger effect than branded ads.  Advertising was also specifically associated with starting testosterone without a prior blood test. (19, 20).

 

At this point it goes without saying that testosterone and other anabolic steroids are considered performance enhancing drugs with other magical properties.  There is a fountain of youth myth and some men claim to take them for anti-aging effects. Excessive use can also occur associated with body dysmorphia and an anabolic androgenic steroid (AAS) use disorder (22, 23).  There is both pre-clinical data to support the use disorder diagnosis but it is not directly recognized in either the DSM or ICD.  Some studies suggest that 30% of casual users will go on to develop dependence on AAS.  It can also be recognized clinically because of the comorbidity with other substance use disorders most notably opioid use disorder.  In treatment settings, supraphysiological doses of testosterone can also be an indication.

 

To summarize, there is a clear indication for testosterone replacement therapy for hypogonadism that requires two fasting morning blood tests with specific cutoffs as noted in the table at the top of this post.  In reality, much more is required because of the causes of primary and secondary hypogonadism that can be both medical (like TBI) or functional (like the stressors of the military environment).  There is no indication for mass screening and no reason to believe that replacing testosterone in men with or without hypogonadism will enhance military effectiveness.  Testosterone has no anti-aging or vitality enhancing properties at physiological doses.  At supraphysiological doses, it is an androgenic anabolic steroid and cause muscle hypertrophy, irritability and aggression, and persistent hypogonadism when withdrawn.  In a study of quality of life in former AAS users abstinent for 2 years – the nonusing strength trainers had a quality of life score comparable to young adults with a previous ischemic stroke (16).

 

Any man considering testosterone replacement should adhere to the guidelines from the endocrine and urological societies.  For those members of the military that may not have a choice – I am hoping that you have access to a VA endocrinologist to make any treatment decisions.  They knew all about it in 1986 when I trained there and have been refining the guidelines for the past 40 years. 

 

George Dawson, MD, DFAPA

 

References:

 

1:  Hennigar SR, Heymsfield SB, Bukhari AS, Lieberman HR, Berryman CE. Testosterone Screening Thresholds in Active-Duty US Male Service Members. JAMA. Published online October 15, 2026. doi:10.1001/jama.2026.19794

 

2:  Health and human performance optimization to enhance military readiness.

Published July 15, 2026. Accessed 10/30/2026.  PDF

 

“Effective immediately, all Active Duty and Reserve Component personnel aged thirty

and older will be screened for testosterone deficiency as a mandatory element of their Periodic

Health Assessment (PHA). Service members under the age of thirty may also request this

screening during their PHA.

 

This enhanced screening protocol directly supports the Department's focus on Human

Performance Optimization while comprehensively addressing Operator Syndrome. Originally

identified among Special Forces in 2020 through collaborative research between the Department

of War (Do W) and leading academic institutions, Operator Syndrome represents a unique

convergence of health challenges that require proactive clinical intervention. Additionally,

applying lessons learned from treating Operator Syndrome across the Total Force including

targeted testosterone therapy directly optimizes Warfighter readiness….”

 

3:  Frueh BC, Madan A, Fowler JC, Stomberg S, Bradshaw M, Kelly K, Weinstein B, Luttrell M, Danner SG, Beidel DC. “Operator syndrome”: A unique constellation of medical and behavioral health-care needs of military special operation forces. The International Journal of Psychiatry in Medicine. 2020 Jul;55(4):281-95.

 

4:  Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT; EMAS Group. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010 Jul 8;363(2):123-35. doi: 10.1056/NEJMoa0911101. Epub 2010 Jun 16. PMID: 20554979.

 

5:  Hennigar SR, Heymsfield SB, Bukhari AS, Lieberman HR, Berryman CE. Testosterone Screening Thresholds in Active-Duty US Male Service Members. JAMA. 2026 Oct 15:e2619794. doi: 10.1001/jama.2026.19794. Epub ahead of print. PMID: 42879141; PMCID: PMC13673370.

 

7: Mubarak, M., Modgil, V. Routine testosterone screening in military personnel: an opportunity for evidence-based implementation in men’s health. Nat Rev Urol (2026). https://doi.org/10.1038/s41585-026-01181-4

 

8:  Friedl KE, Nindl BC, Potter AW. Stress-associated testosterone suppression: central adaptation or hypogonadism? J Clin Endocrinol Metab. 2026 Jul 15;111(8):e1951-e1960. doi: 10.1210/clinem/dgag181. PMID: 42044038; PMCID: PMC13368364.

 

9:  Walker RF, Zakai NA, MacLehose RF, et al. Association of Testosterone Therapy With Risk of Venous Thromboembolism Among Men With and Without Hypogonadism. JAMA Intern Med. 2020;180(2):190–197. doi:10.1001/jamainternmed.2019.5135

 

10:  Selinger S, Thallapureddy A. Cross-sectional analysis of national testosterone prescribing through prescription drug monitoring programs, 2018-2022. PLoS One. 2024 Aug 28;19(8):e0309160. doi: 10.1371/journal.pone.0309160. PMID: 39196907; PMCID: PMC11355536.

 

11:  Pope HG Jr, Wood RI, Rogol A, Nyberg F, Bowers L, Bhasin S. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014 Jun;35(3):341-75. doi: 10.1210/er.2013-1058. Epub 2013 Dec 17. PMID: 24423981; PMCID: PMC4026349.

 

12:  Kanayama G, Hudson JI, DeLuca J, Isaacs S, Baggish A, Weiner R, Bhasin S, Pope HG Jr. Prolonged hypogonadism in males following withdrawal from anabolic-androgenic steroids: an under-recognized problem. Addiction. 2015 May;110(5):823-31. doi: 10.1111/add.12850. Epub 2015 Feb 25. PMID: 25598171; PMCID: PMC4398624.

 

13:  Baggish AL, Weiner RB, Kanayama G, Hudson JI, Lu MT, Hoffmann U, Pope HG Jr. Cardiovascular Toxicity of Illicit Anabolic-Androgenic Steroid Use. Circulation. 2017 May 23;135(21):1991-2002. doi: 10.1161/CIRCULATIONAHA.116.026945. PMID: 28533317; PMCID: PMC5614517.

 

14:  Pope HG Jr, Kanayama G. Body Image Disorders and Anabolic Steroid Withdrawal Hypogonadism in Men. Endocrinol Metab Clin North Am. 2022 Mar;51(1):205-216. doi: 10.1016/j.ecl.2021.11.007. Epub 2022 Feb 8. PMID: 35216717.

 

15:  Bhasin S, Seidman S, Travison TG, Pencina KM, Lincoff AM, Nissen SE, Miller MG, Flevaris P, Li X, Wannemuehler KA, Pope HG. Depressive Syndromes in Men With Hypogonadism in the TRAVERSE Trial: Response to Testosterone-Replacement Therapy. J Clin Endocrinol Metab. 2024 Jun 17;109(7):1814-1826. doi: 10.1210/clinem/dgae026. PMID: 38205962.

 

16:  Pope HG Jr, Kanayama G. Reduced Quality of Life in Former Androgen Users: An Evolving Public-Health Concern. J Clin Endocrinol Metab. 2024 Apr 19;109(5):e1400-e1401. doi: 10.1210/clinem/dgad661. PMID: 37955864.

 

17:  Dubin JM, Jesse E, Fantus RJ, et al. Guideline-Discordant Care Among Direct-to-Consumer Testosterone Therapy Platforms. JAMA Intern Med. 2022;182(12):1321–1323. doi:10.1001/jamainternmed.2022.4928

 

18:  Woloshin S, Gill LL. Direct-to-Consumer Low-Testosterone Clinics—Where Is the Federation of State Medical Boards? JAMA Intern Med. 2023;183(4):288–289. doi:10.1001/jamainternmed.2022.7008

 

19: Kravitz RL. Direct-to-Consumer Advertising of Androgen Replacement Therapy. JAMA. 2017;317(11):1124–1125. doi:10.1001/jama.2017.1364

 

20:  Layton JB, Kim Y, Alexander GC, Emery SL. Association Between Direct-to-Consumer Advertising and Testosterone Testing and Initiation in the United States, 2009-2013. JAMA. 2017;317(11):1159–1166. doi:10.1001/jama.2016.21041

 

21:  Kanayama G, Brower KJ, Wood RI, Hudson JI, Pope Jr HG. Anabolic–androgenic steroid dependence: an emerging disorder. Addiction. 2009 Dec;104(12):1966-78.

 

22:  Kanayama G, Hudson JI, Pope Jr HG. Features of men with anabolic-androgenic steroid dependence: A comparison with nondependent AAS users and with AAS nonusers. Drug and alcohol dependence. 2009 Jun 1;102(1-3):130-7.

 

23:  Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996 Jul 4;335(1):1-7. doi: 10.1056/NEJM199607043350101. PMID: 8637535.

 

 

Supplementary 1:  I was fortunate to train and work with many excellent endocrinologists at the Milwaukee VAMC and at St. Paul-Ramsey Medical Center/Regions Hospital.  I learned a lot in the process and ended up seeing many complex endocrine problems in clinical practice and serving on relevant committees with some of those same endocrinologists. Based on that experience I do not see any potential advantages to consider post TBI hypopituitarism as a feature of another syndrome. I personally saw it diagnosed and treated many times at the Milwaukee VAMC often associated with panhypopituitarism and recognized and treated several of those cases in clinical practice.  They were all secondary to TBI or neurosurgery complications.

 

Supplementary 2:  I was equally fortunate to train and work with many vets.  One of them described Jungle Warfare School to me. I will not attempt to recreate the scenarios he told me about -  and will only say it clearly puts members of the military at risk and places them under extreme physiological stress. The neuroendocrine system has always been an area of research in psychiatry. I was a research fellow in a program where we tested the HPA axis and adrenal responsiveness in patients stressed by depression.  A thorough characterization of some of these stressful training programs may be a batter place to start than just measuring testosterone levels and considering the patient to have hypogonadism.

 

The political atmosphere that these recommendations occur in cannot be ignored.  They are being made by a Department of War Secretary who has taken to lecturing experienced military personnel about fitness for duty and suggesting goals that are long on aggression and short on strategy.  Combined with the DOGE effects of reducing VAMC staffing and medical care I think it is reasonable to be concerned about whether members of the military will get adequate assessments for any abnormal tests rather than just a prescription. Congress should be watching this as an experiment if the guidelines for testosterone replacement are not met and if the effects of testosterone are not carefully followed.