Aging refers to the continuous and slow decline of biological functions in our bodies over time–functions that are necessary for survival, growth, and fertility.
As men age, there are telltale signs of the aging process. These start in the 30s, and appear around:
The skin starts to wrinkle, muscle strength reduces, vital body functions erode, and quality of life suffers with aging. The most common changes men report in their bodies as signs of aging include:
Research on the process of aging is in early stages, however, there are mainly two schools of thoughts.
First one believes aging is part of the natural selection process: once an animal completes reproduction and raises the offspring, it can die. In essence, it has served its purpose in survival of the species.
In contrast, followers of second theory believe in a genetic component. By altering it and adapting to their environments, they believe it is possible to slow down the process.
Considering the slow decline in daily functions, it is natural that people look for possible signs and triggers of the aging process. They desire to monitor and act on them to counter the whole process. Many believe one such sign is the testosterone levels in men.
However, a recent research study that followed 7,671 men and women for 14 years during the Framingham Heart Study did not find any independent correlation of low testosterone to heart disease or heart failure.
The total testosterone levels continuously decline with age, after peaking in mid-twenties. The plot below, from the Institute of Medicine of the National Academies, shows this drop in different age groups from several scientific studies. The number of people in each study is marked next to each line.
Many popular terms describe the gradual decline of hormones in men including adrenopause, somatopause, and andropause. Along with T, this includes DHEA (de-hydro-epi-andro-sterone), DHEAS (DHEA-sulfate), and GH (growth hormone). However, this declining behavior is true for many other physiological processes in the body, not just hormones.
The medical term for low testosterone is hypogonadism.
(Data from National Academies, each line is an independent study showing number of participants.)
The next obvious question is the relationship between age and hormones. Does aging result from low levels? Or, this decline is simply a symptom of getting old?
Data from people using supplements for low testosterone suggest some of these symptoms of aging do improve. However, that’s not always true and generalization is difficult. The research in this field has not conclusively confirmed improvement in symptoms for everyone, however, those with artificially low testosterone levels seem to benefit the most.
In recent years, home based low testosterone saliva tests are gaining popularity. It is recommended that one should understand the available scientific knowledge in order to benefit from them. Hopefully this article, along with summary of scientific research covering all about testosterone will help.
Here we review several scientific studies and try to answer basic questions of how testosterone levels change throughout a man’s life span. We also look at the challenges in measuring testosterone despite a clear dependence on age. Finally, a discussion around the guidelines from FDA and future opportunities for researchers and medical providers follows.
Historically, men considered testosterone as the ‘youth’ hormone. Over hundred years ago, at the time of almost no medical regulation, several people claimed unbelievable health benefits by using testosterone (via self-injections with animal samples).
A recent book by anthropologist Katrina Karkazis and socio-medical scientist Rebecca Jordan-Young explains some of these interesting historical stories and the science behind them.
Things started to change around WWII when Ruzicka and Butenandt independently isolated and synthesized testosterone. Both received the Nobel prize for their achievements in 1939.
Soon, research in this field exploded and first medical product for human use became available in 1950s. However, an oral pill never successfully commercialized since testosterone is weakly soluble in water and difficult to absorb. And the liver rapidly digests it resulting in liver damage.
The focus then shifted to other forms: gels, skin patches, injections, nasal sprays, or gum patches. However, none of them so far have delivered a product that’s safe, effective, and inexpensive. Most still aren’t easy to use or even non-irritant. The search for a product with minimal side-effects, which can deliver doses for prolonged periods, continues.
Due to the ever increasing interest in testosterone, in 1992, the FDA, NIH, and WHO decided to postulate guidelines for a testosterone patch that could be safely used for those with clinically low levels. However, the patches were found to be skin irritant and a better solution was required.
Injections of testosterone in oil suspension were also approved but levels fluctuate significantly from beginning till end. The inconvenience of self-injection or doctor visits limited their adoption.
In 2000, first testosterone gels appeared in the market. These could be easily utilized, however, the constant worry of affecting those coming in contact still remained a problem.
In 2014, the first FDA approved nasal spray for testosterone appeared in market.
Today, over a hundred products including testosterone boosters–supplements that claim to naturally boost the body’s ability to produce testosterone–are available in market.
The average testosterone levels in men vary throughout life. They play a crucial role in the health and development of the human male from conception to well into the old age.
Key changes in testosterone levels in the life cycle of males are:
Source: Age, Disease, and Changing Sex Hormone Levels in Middle-Aged Men: Results of the Massachusetts Male Aging Study by Gray et. al. in The Journal of Clinical Endocrinology & Metabolism, Vol 73 (5), 1 November 1991, Pages 1016–1025.
The Leydig cells in testes produce most of testosterone in men. A small amount is also produced in the adrenal cortex (the surface of adrenal glands that releases other hormones including cortisol).
There are four key players in the production of testosterone as displayed in the graph below:
Source: Testosterone and Aging: Clinical Research Directions (2004) – Consensus Study Report by Institute of Medicine of The National Academies.
Several factors related to age affect the lower levels in older men:
Testosterone production in our body is a complex biological cycle that involves five key steps–and multiple enzymatic reactions–to convert cholesterol into testosterone as the final product. The plasma cholesterol first converts to pregnenolone, and subsequently into progesterone and DHEA, then androstenediol and androstenedione, and finally testosterone.
The enzyme 5-alpha reductase converts some of the testosterone into DHT (dihydrotestosterone) in prostate, skin, and reproductive tissue. Rest of it converts to estrogen in the fat cells and liver. Therefore, in older men, an increase in fat cells might result in higher estrogen conversion.
As the sketch of a blood vessel above shows, only 1-2% of testosterone circulating in the blood is active, free testosterone.
The rest binds to albumin (60%) and SHBG (sex hormone binding globulin; approx. 40%). The albumin part binds weakly and can rapidly dissociate whenever needed. Therefore, together with free testosterone, approximately 42% is available in the body as bio-available testosterone.
Because SHBG increases with age, the ratio of remaining free testosterone decreases in older men.
Similar to cortisol, testosterone levels follow a 24-hour diurnal rhythm, albeit less pronounced. Levels are highest around after 30 minutes of waking up, and then drop throughout the day. The circadian pattern appears less pronounced in older men (Bremmer 1983, Tenover 1998).
In general, levels can vary significantly from person to person and key variables including age, alcohol consumption, smoking, BMI, and exercise need careful review during testing.
A blood or a saliva sample can measure testosterone levels.
The traditional method with blood serum measures
However different methods are necessary for measuring each of them:
Saliva testing of testosterone offers ease of sample collection without the need of a medical professional. As the accuracy of testing improves, it has recently become a popular method. Saliva immuno-assay (or ELISA) can be easily standardized and validated with high reproducibility.
The method has become popular due to multiple reasons:
A CLIA certified lab with well established references is best way to test free testosterone. However, a general lack of awareness among healthcare professionals about the accuracy, reproducibility, and validity has made this method less popular.
For diagnosis of hypogonadism, one should follow the following steps:
The diagnosis can be tricky as low levels may be marker of ill health (not a cause of it). And:
Data from several scientific studies suggest the following general testing guideline:
* Total T <= 200 ng/dL: hypogonadism is confirmed unless serious pituitary and hypothalamic issues
* Total T between 200 and 400 ng/dL: further testing and consideration for therapy
* Total T > 400 ng/dL: no deficiency
* Total T < 320 ng/dL
* Free T < 7 ng/dL
* Bioavailable T: 90 – 230 ng/dL
For our home testosterone test kits from saliva samples, we define a free testosterone value below 5 ng/dL (50 pg/mL on the report) as low and recommend further attention and changes in lifestyle.
Those below 1 ng/dL (10 ng/dL on the report) should test again with a different sample and talk to their primary physician.
The FDA explicitly recommends use of prescription only in certain medical conditions. Hypogonadism (unusually low testosterone levels) is a medical condition resulting from inadequate gonadal function, a deficiency in sperm production, and gonadal hormone secretion. Depending on the cause, it is classified into two types:
The FDA has recognized abuse of testosterone products and has provided guidelines for approval and prescription of testosterone products.
Based on available data, the FDA says those taking therapy are at higher risk of stroke and heart attack like symptoms and should monitor them carefully:
Data from US Census Bureau projects the ratio of older population will keep increasing in foreseeable future. The plot below shows US population projections for 2018 and 2030.
The orange region in this plot forecasts a 15% increase in population of those 30 years and older by 2030. That’s approximately 15 million more men with declining testosterone levels and searching for answers regarding their health outcomes.
That is a strong motivation for scientists, researchers, and medical providers to find better answers. For those serving this market segment, the opportunities are enormous.