Low Testosterone Linked With Mortality Risk in Aging Men - by Jeff Minerd , Contributing Writer, MedPage Today May 13, 2024

[cujoe]

No way to know if this is applicable to those on ADT, but it would seem to be relevant for consideration. The highlighted portion is a useful guide on male sex hormone targets for those testing them. These results might also add support for Morgentaler's "Saturation Model" for testosterone. Full text of MedPage article is below (emphasis added):

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Low Testosterone Linked With Mortality Risk in Aging Men - Meta-analysis examined studies with mass spectroscopy measures, providing greater accuracy, by Jeff Minerd , Contributing Writer, MedPage Today May 13, 2024

A low serum testosterone level at baseline was associated with higher risk for all-cause and cardiovascular disease (CVD) mortality, a meta-analysis of 11 prospective cohort studies found.

In age-adjusted analyses, men in the lowest quintile (8.46 nmol/L [244 ng/dL]) of total testosterone concentration had a higher risk for all-cause mortality (HR 1.09, 95% CI 1.01-1.17) and CVD mortality (HR 1.32, 95% CI 1.06-1.64) compared with men in the highest quintile, reported Bu Yeap, MBBS, PhD, of the University of Western Australia in Crawley, and colleagues.

In fully adjusted analyses that accounted for a host of other potential confounders, however, only men with testosterone concentrations below 7.4 nmol/L (213 ng/dL) had a higher risk for all-cause mortality, and only men with concentrations below 5.3 nmol/L (153 ng/dL) had a higher risk for CVD mortality, according to findings in the Annals of Internal Medicineopens in a new tab or window.

"This is, to our knowledge, the first [individual participant data meta-analysis] of major prospective cohort studies using mass spectrometry sex steroid assays, which clarifies previous inconsistent findings on the influence of sex hormones on key health outcomes in aging men," the researchers wrote.

Yeap elaborated on the significance of the findings in an email to MedPage Today. "These results provide insights on testosterone concentrations expected in healthy men, additional to information from laboratory reference ranges," he wrote.

The study also examined outcomes related to sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Key findings included the following:

Lower SHBG was associated with lower all-cause and CVD mortality

Concentrations of LH above 10 IU/L and estradiol below 5.1 pmol/L were linked with higher all-cause mortality

The study found a U-shaped relationship with DHT and mortality risk

"The association of lower testosterone concentrations with higher all-cause mortality was present irrespective of luteinizing hormone concentrations," Yeap explained, "indicating that low testosterone was the main factor."

Furthermore, men with lower testosterone concentrations and normal or high SHBG had increased mortality risk, but those with lower testosterone concentrations and low SHBG had lower mortality risk, Yeap said. "This is consistent with the fact that men can have lower testosterone concentrations in the presence of low SHBG, without being hypogonadal."

In an editorial accompanying the study, Bradley Anawalt, MD, of the University of Washington School of Medicine in Seattle, said a chief strength of the meta-analysis was its inclusion of studies that used mass spectrometry measurements.

"Mass spectrometry is considered the most accurate method of testosterone measurement and can also be used to measure DHT and estradiol accurately," Bradley said, "whereas widely available commercial immunoassays are inaccurate for measurement of these sex steroids in men, who typically have low serum concentrations of these two metabolites of testosterone."

The 11 studies in the meta-analysis were all prospective cohort studies of community-dwelling men who had sex steroids measured with mass spectrometry and were followed for at least 5 years. The median age of men in the studies ranged from 49 to 76. The researchers obtained individual participant data from nine of these studies, which included more than 20,000 men, and aggregate data statistics from the other two studies, which included more than 3,000 men.

The researchers modeled the testosterone data as a continuous variable, using restricted cubic splines. The primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates for the fully adjusted analyses included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use.\

The men in the studies were predominantly white and from Australia, Europe, and North America, so results should be confirmed in studies involving men of different ethnicities from other geographic regions, the researchers said. Another potential limitation of the meta-analysis was that sex hormones were assayed in different laboratories at different times.

Bradley concluded in his editorial, "Overall, these epidemiologic data support the hypothesis that hypogonadism is associated with higher cardiovascular and/or all-cause mortality. The data also support the free testosterone hypothesis that states that unbound testosterone is the active form of the hormone -- a hypothesis that is somewhat controversial."

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Here is the link to the MedPage Today article:

Low Testosterone Linked With Mortality Risk in Aging Men - Meta-analysis examined studies with mass spectroscopy measures, providing greater accuracy, by Jeff Minerd , Contributing Writer, MedPage Today May 13, 2024

medpagetoday.com/endocrinol...

And the the research paper itself:

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men: Individual Participant Data Meta-analyses, Annals of Internal Medicine, Reviews, 14 May 2024.

acpjournals.org/doi/10.7326...

Much to consider for those on or considering long-term SOC.

Stay S&W, Ciao - Capt'n cujoe

[maley2711]

Well, I'm not sure this would deter many men from SOC ADT use. It is SOC because survival is longer with it than without it....correct?

[cujoe in reply to maley2711]

Maley - That is only true if the patient doesn't die as a result of something else caused by low T - and/or the cumulative known debilitating SEs of ADT - most directly related to the cascading effects of castrate T levels.

[Maxone73 in reply to cujoe]

Yea those are known side effects and risks….we have to choose the lesser of two evils, but I would understand someone with high risk of heart failure refusing SOC…I don’t t even know if he would be offered SOC. I hope we will soon have more data about how to predict who BAT can work for and also some serious study about metabolic diets and so on .

[maley2711 in reply to cujoe]

Don't agree with your conclusion.....ask TA? ADT only used for better results than without ADT.....of course, those are probabilities, and not predictions for any specific man.

[cujoe in reply to maley2711]

Maley - Try this for a better perspective from real researchers - and not bloggers:

Causes of Death Among Prostate Cancer Patients Aged 40 Years and Older in the United States, Frontiers in Oncology, Genitourinary Oncology, Volume 12 - 2022, 30 June 2022.

frontiersin.org/journals/on...

[Don_1213 in reply to cujoe]

@Cujoe - what do you find in this paper relevant to this discussion.. I just scanned through it, and found the only mention of ADT in the summary, and not really mentioning low testoserone. A rather lengthy quote from it:

"The spectrum of cause of death also changed more significantly with increased follow-up time. The risk of non-cancer deaths continued to rise with the extension of survival time. After the 10th year, non-cancer deaths accounted for 67% of all deaths, which was four times that of PCa-specific deaths. Specifically, cardiovascular diseases and chronic obstructive pulmonary disease and allied cond (COPD) were the most common non-cancer causes of death. By 5 years after PCa diagnosis, the proportion of deaths from cardiovascular diseases exceeded that of deaths from PCa (Table 3). Several previous studies using the SEER program have shown that cardiovascular diseases and COPD are the most common non-cancer causes of death in the cancer patients in the United States, especially PCa patients (8, 9, 29). In a cohort study of 15,878 patients from Denmark, the most common non-cancer cause of death in PCa patients was cardiovascular disease, accounting for 17.0% of all deaths (12). There may be several reasons for this significant change. ADT is the main treatment method for patients with metastatic PCa. Studies have shown that patients receiving ADT have a higher incidence of cardiovascular disease and mortality (30, 31), which may be due to its metabolic effects (32)."

Did you find something I missed in that paper?

[maley2711 in reply to cujoe]

I reviewed that , and little to do with the benefit of using ADT. Basically, you are claiming that use of ADT decreases the life expectancy of high risk and metastasized patients...correct? If not, what are you claiming?

[maley2711 in reply to cujoe]

Yes.....to the extent we have data for ADT use for men with specific comorbidities.......for example, fo men , like me, who arr very close to osteoporisis definition.....T score -2.2...yikes. Ihaven't asked any Doc about such data...probably doesn't exist. My risk of major fracture without consideration of T level is already 20% over 10 years...13% risk hip fracture over 10 years. FRAX calculator has no input for cancer status and treatment!!! So a guessing game...too much risk to justify use of ADT with RT for Gleason 4+5??????????????????????? Or as SOC for proven metastases?

If you KNOW the answer, please let me know ASAAP!!!!!!!!!!!!!!!!!!!

[NPfisherman in reply to maley2711]

Maley,

Intermittent ADT is noninferior to continuous ADT in terms of OS... pr7 was an old trial..

medscape.com/viewarticle/87...

The question that needs answered is whether continuous is equal to intermittent in regards to stroke, heart attack, etc... ADT and abiraterone turned me into a hormonal desert....T down estradiol down, DHT, etc... as an "unnatural" state, this does not do well for patients in a variety of medical/metabolic issues:

youtube.com/watch?v=cX-4AC4...(Not working as expected?)

I think Scholz does a good video on intermittent... As he says, it is not for everyone... but it does makes sense for some..

DD

[Don_1213]

That article caught my eye also - since I had a discussion with my medical oncologist, at the suggestion of my primary care MD. My primary-care guy (been going to him for more than 30 years) suggested I talk with my MO since my T, which recovered to low 80 year old level about 6-8 months after Lupron was done with, has been slowly but inexorably dropping since then.

I'm now below 180. At the same time - my PSA has been constant since I came off ADT, running from 0.15-0.23 - little ups and downs, but it's basically been a flat line, which my MO thinks is a very good thing.

In about a month or so - I'll be 78,

I have rather severe spinal stenosis, combined with osteophytes blocking nerve exits from the spine, and toss in peripheral artery disease - well - walking is really not pleasant at all, neither is standing around.

I do the gym - used to do every day, then 3 days a week.. it doesn't seem to help and frequently after a fairly hard (for me) gym workout I have pain that wakes me up in the middle of the night.

I also have 6 stents, and my cardio guy is thinking another cardiac catheterization session might be in order with the stent guy in attendance.

My primary care guy thinks much of this might be helped if I had some energy, and the lack of energy may be linked to the low testosterone level.

SO - I had that talk with my MO a little over a week ago - and he and I discussed positives vs negatives (obvious one would be a PCa recurrence) how to do it and how to monitor it if I do it and what I might expect. My MO's feeling was - my situation falls on the positive side of the equation for me given my existing comorbidities. As the paper mentioned above makes reference to - it might just help avoid - at least delay for some time - a heart attack or stroke.

I read the paper a few times, printed it out, sent it to my MO. His plan is to hook me up with a specialist on hormonal treatment, not just slap a patch on me and call it good. He wants me to have at least monthly PSA and T tests, and in the beginning perhaps every other week. As long as I'm on the T supplement the monthly tests will continue. And we'll see if it does any good.

That's what triggered my interest in the study..

[cujoe in reply to Don_1213]

Don - I assume you are familiar with Dr. Abraham Morgantaler's "saturation model" regarding testosterone "fueling" PCa. If not, here are a series of talks by him from the Androgen Society in 2021, SPCS 2019, and 25th International Prostate Cancer Update (2015). These talks are provided by the excellent Grand Rounds in Urology website. In these various talks, Dr. Morgantaler discusses the model, how he came to develop it, and his clinical experience with TRT in older men. (The last audio of the talk he gave in 2015 is especially good, as it chronicles how he came to question the role of testosterone and PCa.)

Grand Rounds in Urology, Abraham Morgentaler, MD, FACS.Men's Health Boston, Boston, Massachusetts

grandroundsinurology.com/au...

Dr. Morgantaler has almost single-handedly debunked the notion that TRT would be like adding "gasoline to the fire" where PCa is concerned. As with most who challenge SOC, he was marginalized for much of his career. The success of BAT has only recently restored credibility to a doctor who was brave enough to look beyond the status-quo of his peers.

These are talks that ALL PCa patients should view, as it will allow them to expand their thinking beyond ADT as the best/only treatment approach for PCa. When considering QOL, it is undebatable that denying men of their principal sex hormone has anything other than negative consequences.

I like to often repeat here what one of the co-founders of a patient support organization for my other (1st) cancer likes to say: "Smart Patients Get Smart Care™".

Get Smart to Stay/Be Well,

Ciao - cujoe

[j-o-h-n]

"Smart Patients Get Smart Care™".

"Dumb Patients Don't Really Care™".

Good Luck, Good Health and Good Humor.

j-o-h-n

[cujoe in reply to j-o-h-n]

Definitely a lot more of those around™!

[NPfisherman]

Dog of Terror,

Thanks for posting.... mine is rising slowly, but my other labs are good for now... monitoring it all... I have thought I may take a dose of T ,,, watchin' the numbers...

DD

[cujoe in reply to NPfisherman]

NP - I think the free-T is the important number. My total T is regularly in the 800s, but my free-T is ~ +/- 1% - i.e., last labs had me with a total of 827 and an out-of-range low free-T of 5.2, which works out something around 0.6 %!!! I've only tested SHBG once (it was way high) and, as it and albumin bind most T, I don't expect I will ever come close to the 2% free that most consider to be optimum for men's health. (Sometime back, when I mentioned the very high SHBG and low free-T to our old friend, Nal, he said his also ran high and he considered it to be a positive - as T that is "bound" is not "free" to be biologically active elsewhere.)

I don't remember Morgantaler's "saturation" number for T exactly, but I think something over 250 ng/dL clears his model's number. If you don't get above that relatively quickly, there could be an argument for TRT of some form. But the how, what, and when of doing that is something I have zero knowledge about.( BTW, it would be interesting to know if Morgantaler bases his model on free-T being ~ 2%?)

Are you north or south for the holiday? Have a nice one either place - and safe travels, if you are on the road. Keep it S&W. Ciao - Capt'n cujoe

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This paper might also be of interest to you:

A Reappraisal of Testosterone’s Binding in Circulation: Physiological and Clinical Implications, Endocr Rev. 2017 Aug 1; 38(4): 302–324.Published online 2017 Jun 29.

ncbi.nlm.nih.gov/pmc/articl...

[NPfisherman in reply to cujoe]

K9 Hormone Dog,

My Free T was 1.1.... T is 236... DHT is low...SHBG was 70... Feeling normal again...

DD

[cujoe in reply to NPfisherman]

Well, your free percentage is even lower than mine. But it might just be normal for the free-to-total percentage to be that low during the T-recovery period after longer-term ADT.

You may remember, that I have done two short-term lupron treatments, the 1st a typical 3 mo depot after BRC#1 (that got me an almost 4-year treatment vacation) and the 2nd, two single month shots after the 2021 BCR#2. Both times I got rather spectacular T rebounds 60 to 90 days after the effective end of treatment, but with your longer treatment cycle, there is little doubt it will take you more time to get back up into the middle of the normal range. (Which seems too wide to be useful anyway!)

Patience, Young NP Grasshopper. Patience!

PS - I could send you a week's worth of bical and that might jump-start the T rise!

[NPfisherman in reply to cujoe]

Terror Dog,

Patience indeed !!! I decided to wait for now, as the washout period for ADT drugs can be a while. I believe it is about normal for the current T, so I am ok with that, and SHBG is on the upper end of normal... I will pass on the bical for now, although a natural T stimulator may be considered (anyone got a recommendation??)... an injection is also under consideration ... but not rushing anything... except QOL events...

DD