Is Low Testosterone Genetic? Uncovering The Facts

Recent research shows that low testosterone might be linked to our genes. Your genes are like instructions for your body, made up of DNA. Even small changes in this DNA sequence, called genetic variants or polymorphisms, can lead to big problems in how genes work. This can affect how cells function and cause diseases.

While low testosterone isn't purely a genetic condition, certain genes have been linked to it. These genes are called "genetic markers" and can increase the chances of having low testosterone. One study found that men with three or more of these genetic markers are almost seven times more likely to have low testosterone.

The study looked at nearly 9,000 men with low testosterone and found a connection with a protein called sex hormone-binding globulin (SHBG). Men with a particular genetic variation in the SHBG gene have a much higher risk of developing hypogonadism, which is when the body doesn't produce enough testosterone.

Variants in the SHBG gene are the main ones linked to low testosterone, but many genes are involved in making and responding to testosterone. So, changes in any of these genes could mess with testosterone levels in the body.

Lots of other genes have been linked, too. A study looked at data from around 150,000 men with low testosterone from the EU Biobank. They found 141 spots on genes like JMJD1C, LIN28B, LCMT2, ACTN3, and ZBTB4 that might be linked to low testosterone. These changes could act as clues to figure out how likely a guy is to develop hypogonadism.

Changes in the SHBG gene are the most understood genetic factors linked to low testosterone. This gene makes a protein called SHBG, which helps move testosterone and other sex hormones around the body.

About 70% of testosterone in the bloodstream sticks to SHBG, and another 20% to 30% sticks to a protein called albumin. The body can't use this bound testosterone; only about 2% (the "free testosterone") can do its job. So, SHBG is super essential for controlling how much testosterone is available.

Different versions of the SHBG gene can affect how much SHBG protein and testosterone are in the blood. Here are some examples:

Rs1799941: This version increases SHBG gene activity and production of the SHBG protein. More SHBG means less free testosterone available for the body to use.

Rs6258: This version makes SHBG stick to testosterone more tightly, so less free testosterone is available. This can lower overall testosterone levels in the blood.

Rs5934505: This version is linked to lower blood testosterone levels and a higher risk of late-onset hypogonadism, possibly because it changes how androgens (like testosterone) signal to muscles.

Even though SHBG changes are the most studied about low testosterone, other genes like JMJD1C, LIN28B, LCMT2, ACTN3, and ZBTB4 are also connected to the condition.

JMJD1C Gene: This gene makes a protein that interacts with thyroid hormone receptors. Certain changes in the JMJD1C gene, like the ones labelled rs7910927 and rs10822184, can lower levels of SHBG and testosterone.

LIN28B Gene: This gene produces a protein that controls how genes are used. It seems that LIN28B helps control sex hormone pathways, and having high levels of it might lower testosterone. So, changes in LIN28B could be linked to low T.

LCMT2 Gene: This gene also plays a role in gene activity and might affect testosterone production. Scientists found seven changes in this gene that could be linked to low testosterone.

ACTN3 Gene: This gene is found in muscles and helps with solid muscle movements. People with a specific version of this gene (XX) have been seen to have lower testosterone levels, which might hint at a risk for low T.

ZBTB4 Gene: This gene does many things inside cells, like triggering responses and controlling genes. While its role in androgen metabolism isn't clear, some changes in this gene seem to boost its activity and could be connected to low testosterone.

Genetic conditions happen when your genes change. You'll have the disorder if you have the "faulty" gene. These genes can be passed down from parents or can happen because of changes in your DNA during your life.

Hypogonadism isn't a genetic condition because having genetic markers doesn't mean you'll have low testosterone—you're just more likely to. However, some rare genetic disorders can lead to low testosterone as one of the symptoms. If you have any of these genetic disorders, your testosterone levels might be lower than they should be.

Klinefelter’s Syndrome

When babies are born, their sex is determined by X and Y. Girls have two X chromosomes (XX), while boys have one X and one Y (XY). But in Klinefelter's syndrome, guys are born with an extra chromosome, making them XXY. This is rare, happening in about 1 in every 660 men.

Even though they have the Y chromosome, which typically makes someone male, guys with Klinefelter’s often have wider hips, less facial and body hair, and sometimes develop breast tissue (called gynecomastia). Their testosterone levels are usually low because their testes don’t develop right.

Noonan Syndrome

Noonan syndrome is a genetic condition caused by problems in eight different genes. It can be passed down from parents, but sometimes, it happens randomly because of a genetic glitch.

The severity of Noonan syndrome can vary a lot. Some people might not even know they have it, while others might have severe symptoms that can be life-threatening. It mainly causes developmental issues and heart problems, but in guys, it can also lead to low testosterone and trouble having kids.

Kallmann Syndrome

Kallmann syndrome is a genetic disorder where there's not enough gonadotropin-releasing hormone (GnRH). This hormone is super vital for making testosterone. GnRH tells the pituitary gland to make and release luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which then tells the testicles to make testosterone.

But when there's not enough GnRH, this whole process gets messed up, and testosterone production goes down. So, guys with Kallmann syndrome have low testosterone levels. They might have symptoms like low sex drive, trouble getting or keeping erections, losing muscle mass, and not being able to have kids.

Prader-Willi Syndrome

Prader-Willi syndrome (PWS) occurs when some genes are missing. It's not usually inherited, but sometimes, it's a random mistake in the DNA. Still, there's a minimal chance it can happen again in a family.

With PWS, the missing genes often cause low testosterone, which happens in almost all guys with PWS. This can be because of problems with the testes (primary hypogonadism), signals from the brain (secondary hypogonadism), or both.

Myotonic Dystrophy

Myotonic dystrophy is a disease passed down in families because of problems in the Y chromosome. It weakens muscles and causes stiffness, slow heartbeats, and trouble swallowing and going to the bathroom. Symptoms can be mild or severe.

People with myotonic dystrophy often have much lower testosterone levels, and their testicles might shrink. About two-thirds of them have low testosterone. Even though giving testosterone helps with the symptoms of low testosterone and builds up muscle, it doesn't make muscles stronger in myotonic dystrophy.

Research shows that low testosterone (low T) can be influenced by genetics, with certain genes acting as markers for high-risk individuals. Additionally, some genetic conditions can lead to low testosterone as a symptom. However, it's not just about genes—your environment also significantly influences your risk of developing hypogonadism.

A study from the University of Durham suggests that testosterone levels in males are shaped by their childhood living conditions rather than solely by genetics. Men who faced more challenging circumstances during childhood, like living in poverty or being exposed to infectious diseases, tend to have lower testosterone levels compared to those who grew up in healthier environments.

While genes aren't the sole cause of hypogonadism, environmental factors can impact your risk of developing low T. Here are some environmental factors linked to the condition:

Diet & Exercise:

Poor diet and lack of exercise can lead to weight gain and obesity, which are strongly associated with low testosterone in men. Fatty tissues can convert testosterone into estrogen, and increased body fat can accelerate this conversion, causing testosterone levels to drop. Conversely, consuming foods rich in testosterone-boosting nutrients like magnesium, zinc, and vitamin D can help improve testosterone levels and reduce the risk of hypogonadism.

Chemical Exposure:

Low testosterone has been linked to exposure to various chemicals, including pesticides, air pollution, and radiation. These environmental factors can cause oxidative stress, a condition resulting from excess free radicals in the body. Increased reactive oxygen species (ROS) levels could alter testosterone levels.

Access to alcohol at home can increase the risk of alcohol abuse, which can negatively affect male reproduction and testosterone levels in several ways:

Leydig Cell Function: Alcohol can harm Leydig cells in the testes, which produce and release testosterone. More alcohol consumption leads to less testosterone production and secretion.

Pituitary Hormones: Alcohol reduces the production and release of LH and FSH hormones in the pituitary gland. These hormones signal the testes to make testosterone. So, the more alcohol you drink, the less testosterone your body produces.

Poor sleep quality and insufficient sleep have been linked to low testosterone levels.

Studies have shown that individuals sleeping for shorter durations, such as five hours per night, experience a 10% to 15% reduction in testosterone levels compared to those sleeping eight hours per night. Factors influencing sleep quality
include the sleep environment, such as light, noise, temperature, and bed comfort.

Conditions like obstructive sleep apnea (OSA), often associated with excess weight and obesity, are also linked to decreased testosterone levels in men, emphasizing the importance of both sleep and diet in maintaining hormonal balance.

Low testosterone can stem from genetics, environmental factors, or both. However, regardless of the cause, testosterone replacement therapy (TRT) is often the preferred treatment option for alleviating unwanted symptoms.

Our tests evaluate free and total testosterone levels and other vital biomarkers to assess your qualification for treatment. Please note that our tests do not provide genetic information, so a karyotype genetic test is required.

If you need help with testosterone-related concerns, you can contact Androgenix for assistance and guidance. We specialise in addressing issues related to testosterone levels and can provide personalised support to improve your health and well-being.

Mørup, N., et al. Polymorphisms in JMJD1C are associated with pubertal onset in boys and reproductive function in men.

Leinonen, J. T., et al. LIN28B affects gene expression at the hypothalamic-pituitary axis and serum testosterone levels.

Fantus, R. J., et al. Genetic Susceptibility for Low Testosterone in Men: Data from the UK Biobank.

Ahmetov, I. I., et al. ACTN3 genotype is associated with the testosterone levels of athletes.

Griggs, R. C., et al. Lack of Relationship of Hypogonadism to Muscle Wasting in Myotonic Dystrophy.

Roychoudhury, S., et al. Environmental Factors-Induced Oxidative Stress in Hypogonadism and Erectile Dysfunction.

Kim, S.-D., & Cho, K.-S. Obstructive Sleep Apnea and Testosterone Deficiency.