Mitochondrial dysfunction undermines sex hormone production
Summary
Despite accounting for factors like smoking, obesity, age, physical activity and alcohol use, the total testosterone in American men has declined significantly over the last several decades, across all age groups.
Because testosterone synthesis begins in the mitochondria, the most likely culprit for the long decline is an increasing rate of mitochondrial dysfunction.
Insulin resistance, a key marker of impaired mitochondrial function, is associated with low testosterone.
By stimulating mitophagy and mitobiogenesis, cold therapies rejuvenate mitochondria and increase rates of testosterone production.
A Catastrophe in Slow Motion
Total testosterone in men of all ages has been declining for decades. Now, as many as half of adult American men may suffer from low or insufficient testosterone. For example, when researchers examined blood sample data collected from the Center for Disease Control (CDC) in the United States, they discovered that total testosterone had declined by about one-third from 1999 to 2011 in all age groups studied. Moreover they found that in 2016, more than 20% of male adolescents and young men had testosterone levels less than 300 ng/dl, which is the threshold most doctors would consider low, despite the fact that these young men in their teens and early twenties are supposed to be experiencing their peak testosterone years (Lokeshwar et al. 2021).
When the researchers removed confounding factors like smoking, body mass index (obesity), age, physical activity, and alcohol use, they still found a significant decrease in total testosterone in all age groups. What's worse is that the declines have persisted for decades and might be getting worse.
For example, it is well known that men typically suffer lower testosterone levels as they age. That is, older men are expected to have less total testosterone in their blood stream than younger men. However, according to data collected by the Massachusetts Males Aging Study (MMAS), the rate of decline as men age has accelerated. In the 1980's, a 70 year-old could expect to have about 90% of the total testosterone typical of a 45 year-old. By 2002, that figure dropped to about 75% (Travison et al. 2007).
In other words, testosterone levels have been dropping much faster in older men than they were in younger men. That's a serious problem, because low testosterone is associated with a myriad of mental and physiological health issues, including an increased risk of major depression, impaired sexual function, decreased quality of life, and increased mortality.
Speculation about the cause of the decline includes increasing exposure to estrogenic toxins from plastics, more sedentary lifestyles leading to greater obesity, more widespread use of marijuana, and a cultural shift towards characterization of traditional masculinity as "toxic" in a way that encourages men to be more feminine. Those explanations suffer from two shortcomings:
They fail to benefit from an understanding of how testosterone is synthesized within the body, and
The older men who have suffered the greatest decline are not likely to be the cohort most engaged in marijuana abuse, video game addiction, or cultural feminization.
Partly for these reasons, I think all of the speculation about toxins and lack of exercise is wrong. In my opinion, the reason testosterone levels in American men have suffered such a precipitous and dangerous decline is because of increasing levels of mitochondrial injury.
Testosterone is Synthesized in the Mitochondria
Most people don't realize that mitochondria are indispensable for the synthesis of testosterone. Even your medical doctor might fail to recognize that the whole process of testosterone production begins with cholesterol.
The very same cholesterol that most medical doctors will tell you is dangerous to your health is the substrate from which your essential sex hormones are derived.
The chemical formula for cholesterol already contains the core structure that constitutes testosterone. The most important chemical change is cleaving off a hydrocarbon chain from a polycyclic backbone to convert cholesterol into a steroid called pregnenolone. Eventually, the pregnenolone converts to DHEA and other steroidal precursors, until eventually becoming testosterone.
The enzyme responsible for the cholesterol cleavage is called P450scc and it exists predominantly within the mitochondria. Although that might suggest that it is synthesized via mitochondrial DNA, experiments in mice and other models have indicated that genes inside the nucleus are responsible for P450 expression, and that other mechanisms are required to transport P450 enzymes to the inner mitochondrial membrane, where they perform their cholesterol modifying function.
Several lines of evidence suggest that healthy mitochondrial function is critical to steroid synthesis. Because more pregnenolone means more DHEA, which means more testosterone, if mitochondria perform an essential function in maintaining adequate levels of testosterone, then we should be able to observe that exposures that damage mitochondria also suppress testosterone and the opposite. That is, we can hypothesize that therapies effective for restoring mitochondria would boost testosterone.
Insulin Resistance is Associated with Low Testosterone
Although there may be several markers of impaired mitochondrial function, the most salient is a condition called insulin resistance. Insulin is a hormone secreted by specialized cells within the pancreas that aids in the transport of glucose from the bloodstream into cells. For example, Type 1 diabetes is an autoimmune disorder that results in destruction of these specialized, insulin-producing cells. While the Type 1 diabetic may appear normal in all other respects, without insulin, they lose the capacity to metabolize glucose. Chronic hyperglycemia (high blood sugar) and associated complications can result. What's more, without regular injection of exogenous insulin, the Type 1 diabetic operates in a static fat-dominated metabolism that produces ketones as an intermediate metabolic product resulting from fat burning. Left untreated, the lack of insulin can result in a dangerous metabolic state called ketoacidosis, in which ketones are being produced faster than they can be metabolized or eliminated in the urine. The excess ketones can drop the pH of the bloodstream, causing the diabetic to fall into a coma that ultimately results in death. I wrote about my experiences with ketoacidosis when my son was diagnosed with Type 1 diabetes in my article Ice Bath for Fast Keto.
Because insulin has a modulating effect on blood glucose levels, it is often prescribed to Type 2 diabetics. However, the mechanisms of Type 2 diabetes are very different from Type 1, even though they are both characterized by hyperglycemia. In Type 2 diabetics, cells that would ordinarily respond to the action of insulin by allowing transport of glucose to the cell interior where it can be processed by mitochondria instead resist the action of that insulin. As a result, the glucose stays in the blood stream longer, and the pancreas produces even more insulin in an effort to overcome that resistance. The consequence is typically a condition called hyperinsulinemia (excess insulin) that is ultimately associated with every leading cause of death from chronic illness in the United States.
Giving a Type 2 diabetic insulin is like giving an alcoholic a glass of wine. Just like giving the alcoholic a glass of wine isn't going to solve the alcoholism, giving a Type 2 diabetic insulin isn't going to resolve the disease (of hyperinsulinemia). - Brigham Young University Professor Ben Bikman
One of the best blood markers of insulin resistance is high triglyceride to HDL cholesterol ratio. For example, in August 2018 I got my blood tests back showing that eight months of ice baths had reduced my prostate specific antigen (PSA) test from 7.0 to 1.5 ng/mL and boosted my total testosterone levels from mid-700's to 1180 ng/dL. I wrote about those results in What Happened to My Testosterone After Using Ice Baths for My Prostate, but until now I'd never written about what happened to my triglyceride/HDL cholesterol ratio.
An unhealthy ratio is anything above 3.0 and an excellent ratio is anything below 1.0. In August 2018, when my testosterone and luteinizing hormone (LH) peaked at abnormally high levels, my triglycerides measured 32 mg/dL and my HDL cholesterol were 71 mg/dL, which put my ratio at a miniscule 0.45, indicating outstanding insulin sensitivity. What's more my HbA1c (a measure of how frequent blood spikes occur) dropped from from 5.3% in December of 2017 to 4.9%.
Eight months of daily ice baths dropped my PSA, boosted my total testosterone, and reduced my blood glucose readings.
Epidemiological data agrees with my experience. When Korean researchers examined the blood labs of more than 1000 men older than 45 years old, they found that high triglyceride/HDL ratios were associated with a much greater risk of low total testosterone levels (Chung et al. 2020). Similar results were obtained in a larger study of more than 7000 Korean men (Lee et al. 2022).
This is a serious finding, because the insulin resistance is associated with obesity, dementia, heart disease, cancer, stroke, non-alcoholic fatty liver disease, sexual dysfunction, and other conditions sometimes confused or associated with getting older. However, we could also say that insulin resistance is an adaptive response by the cells of the body that protects damaged mitochondria from the overwork of processing too much glucose too fast. That is, becoming resistant to the action of insulin gives damaged mitochondria time to recover and process an excess load of carbohydrates. As a temporary measure to permit mitochondrial recovery, insulin resistance might make sense for overall longevity. The problem is that chronic mitochondrial damage will eventually kill you.
There are at least three routes to mitochondrial injury:
Excess carbohydrates, without periods of fasting or ketosis. The chronic carbohydrate overload results in mitochondrial overwork and production of reactive oxygen species (ROS) that can damage mitochondrial DNA (mDNA). A little bit of ROS can be a good thing, because it stimulates production of new mitochondria in a process called mitobiogenesis. However, chronic exposure to ROS interferes with mitochondrial recovery and leads to metabolic dysfunction.
Poor light hygiene. mDNA is protected from ROS by melatonin, which deactivate ROS by serving as an electron donor (Reiter et al. 2017). However, when melatonin levels are inadequate, ROS will scavenge electrons from mDNA instead, leaving the mitochondria damaged and dysfunctional. Because dark nights are essential for melatonin production, too much light -- especially blue light -- after sunset will disrupt melatonin production and leave mitochondria vulnerable to injury.
Excess seed oils. Because mitochondria are organelles that exist inside of other cells, the proper function of mitochondria depends on three membranes: 1) the cell membrane, 2) the outer mitochondrial membrane, and 3) the inner mitochondrial membrane. For example, the P450scc enzymes that cholesterol to the steroidal precursors to testosterone are found bound to the inner membrane. All three membranes are made up of molecules called phospholipids, which are made up of complex assemblies of fatty acids. The source of these fatty acids is dietary fat. While most people think that food fats are used exclusively for energy, it turns out that much of the fat we eat is incorporated into membrane structures in the body. When eating an ancient diet in which most of those fats come from meat and fish, the distribution of omega-6 to omega-3 fats is about 1:1. However, when eating a modern diet of ultra-processed foods containing soybean, cottonseed, corn and other seed oils, the ratio is more like 20:1. As a result, the cell and mitochondrial membranes must be constructed with omega-6, rather than omega-3 fatty acid building blocks. Disordered membrane transport processes can result.
Given the association between mitochondrial dysfunction and low testosterone levels, it should be no surprise that a group of Chinese researchers discovered that sugar-sweetened beverages reduced serum testosterone levels in young adult American males (Chen et al. 2018). Using data from the National Health and Nutritional Examination Survey (NHANES), they discovered that those who consumed more sugar-sweetened drinks were more likely to have low testosterone levels -- even after correcting for confounding factors like high body-mass index (BMI). Because liquid sugar is notorious for generating ROS in mitochondria and a reliable precursor to insulin resistance, these findings are exactly what the mitochondrial damage hypothesis of low testosterone would predict. Moreover, the opposite is also true. That is, a low carbohydrate diet combined with intermittent fasting was shown to nearly double total testosterone -- at least in one 23 year old man who submitted to an exhaustive, 13-week-long-study (Dynka et al. 2023).
Cold therapies improve testosterone levels
In Ice Baths for Mitochondrial Therapy I explained the way that cryotherapy can initiate both the removal of damaged mitochondria (mitophagy) and the generation of new, healthy mitochondria (mitobiogenesis). Given the beneficial effect that cold has on mitochondria, than we should expect to see a beneficial testosterone effect resulting from cold therapies.
We do.
Several studies have measured this effect, in both men and women. However, important differences between the sexes exist. In men, cryotherapy alone or after exercise will result in a reduction in total testosterone. For example, a Chinese study exposed eight young men to -130C for 150 seconds and discovered lower testosterone both immediately after, 30 minutes after, and two hours after the exposure. However, the tests were conducted in the morning, when serum testosterone levels are typically at the highest point of the day, so some decline is to be expected. In fact, compared to a control group the cold-exposed men exhibited less decline at the two-hour mark. By contrast, a Japanese study showed that cold stimulation prior to exercise resulted in an immediate boost to total testosterone and to luteinizing hormone (Sakamoto et al. 1991).
In women, there is no need for exercise after cold stimulation to obtain an immediate testosterone boost.
I've covered the results of documented case studies and clinical trials in my other articles. Rather than repeat those, I'll post the links:
References
Chen L, Xie YM, Pei JH, Kuang J, Chen HM, Chen Z, Li ZW, Fu XY, Wang L, Lai SQ, Zhang ST. Sugar-sweetened beverage intake and serum testosterone levels in adult males 20–39 years old in the United States. Reproductive Biology and Endocrinology. 2018 Dec;16:1-7.
Chung TH, Kwon YJ, Lee YJ. High triglyceride to HDL cholesterol ratio is associated with low testosterone and sex hormone-binding globulin levels in middle-aged and elderly men. The Aging Male. 2020 Apr 2.
Dyńka D, Paziewska A, Kowalcze K. Keto menu–effect of ketogenic menu and intermittent fasting on the biochemical markers and body composition in a physically active man—A controlled case study. Foods. 2023 Aug 26;12(17):3219.
Fantus RJ, Greenberg DR, Chang C, Helfand BT, Xu J, Wei J, Shoag JE, Nangia AK, Brannigan RE, Halpern JA. Novel reference range values for serum testosterone: a cross-sectional study of 200,000 males. Journal of endocrinological investigation. 2024 Feb 22:1-8.
Kelly KR, Arrington LJ, Bernards JR, Jensen AE. Prolonged extreme cold water diving and the acute stress response during military dive training. Frontiers in physiology. 2022 Jul 8;13:842612.
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Lee JH, Jung HD, Choi JD, Kang JY, Yoo TK, Park YW. Non‐linear association between testosterone and LDL concentrations in men. Andrology. 2023 Sep;11(6):1107-13.
Lokeshwar SD, Patel P, Fantus RJ, Halpern J, Chang C, Kargi AY, Ramasamy R. Decline in serum testosterone levels among adolescent and young adult men in the USA. European urology focus. 2021 Jul 1;7(4):886-9.
Miller WL. Steroid hormone synthesis in mitochondria. Molecular and cellular endocrinology. 2013 Oct 15;379(1-2):62-73.
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Papadopoulos V, Miller WL. Role of mitochondria in steroidogenesis. Best practice & research Clinical endocrinology & metabolism. 2012 Dec 1;26(6):771-90.
Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cellular and molecular life sciences. 2017 Nov;74:3863-81.
Sakamoto K, Wakabayashi I, Yoshimoto S, Masui H, Katsuno S. Effects of physical exercise and cold stimulation on serum testosterone level in men. Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene). 1991 Jun 15;46(2):635-8.
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Travison TG, Araujo AB, O’Donnell AB, Kupelian V, McKinlay JB. A population-level decline in serum testosterone levels in American men. The Journal of Clinical Endocrinology & Metabolism. 2007 Jan 1;92(1):196-202.
Zhao Z, Sun K. Change of Serum testosterone and endocrine indexs after cryotherapy in different age groups. Exercise Biochemistry Review. Proceedings of IBEC 2018. OR-038. 2018 Oct 4;1(2).
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About the Author
Thomas P Seager, PhD is an Associate Professor in the School of Sustainable Engineering at Arizona State University. Seager co-founded the Morozko Forge ice bath company and is an expert in the use of ice baths for building metabolic and psychological resilience.
Anecdotal but here in nyc I’ve
been sleeping in a 60 degree room for 2 months now, going for winter walks, and in the summer that passed I’ve went ocean swimming maybe 10-15 times.
My first ever testosterone test showed 1150, I wish I had a baseline before that but I don’t.
I also have very high cholesterol at 269, but my HDL is 100 too.
I eat mostly a quality high fat diet with potatoes for carbs.