Monday, March 25, 2019. Author Dr. Haran Sivapalan
Monday, March 25, 2019. Author Dr. Haran Sivapalan
Testosterone is the primary male sex hormone.
It’s worth unpicking each of those terms before we describe the functions of testosterone. Let’s start with the term “hormone.”
Hormones are chemical messengers that are produced by glands and regulate various bodily processes. Examples of hormones include: insulin, which helps control blood sugar levels; adrenaline, which facilitates our ‘fight or flight response’; and thyroxine, which influences our metabolic rate.
“Sex hormones” are a particular type of hormone that regulate the growth and function of reproductive organs (e.g. ovaries and testes). They also heavily influence the development of secondary sexual characteristics - physical changes (not directly required for reproduction) that occur during puberty and differ between the sexes. Examples of secondary sexual characteristics include the development of breasts in females and the growth of facial hair in males.
Testosterone is the sex hormone that is key to the development of male secondary sexual characteristics. (By contrast, female secondary sexual characteristics [e.g. breast tissue, wider hips] are largely brought about by two other sex hormones, estrogen and progesterone.)
Testosterone is central to the deepening of voice, increased muscle mass, and the growth of body hair observed in males during puberty. Owing to these effects, we classify testosterone as an androgen – a group of hormones that cause the development of ‘male’ characteristics. Despite this definition, it’s important to note that both males and females produce and require androgens (including testosterone) for various essential functions in the body (these are discussed later).
Apart from testosterone, other key androgens include: androstenedione, DHT (dihydrotestosterone), DHEA (dehydroepiandrosterone), DHEA-sulfate and androsterone.
We can further classify sex hormones based on their molecular structure into protein hormones and steroid hormones. Protein sex hormones, as their name suggests, are made from larger protein molecules and include FSH (follicle-stimulating hormone), LH (lutenizing hormone) and prolactin.
By contrast, steroid sex hormones (or simply ‘sex steroids’) are much smaller, fat-soluble molecules that are originally made from cholesterol. Cholesterol is a fat like substance found in some foods and produced by the liver. In humans, the sex steroids include, estrogens (which comprises estradiol, estrone and estriol), progesterone and, of course, testosterone.
As sex steroids are made from cholesterol, some fat in your diet is important to ensure your body can make adequate amounts of testosterone.
Steroid hormones, by virtue of being fat soluble, can easily penetrate the outer membranes and enter inside cells. They then exert their various effects by binding to steroid receptors, which are typically found within cells. Testosterone (and other androgens) bind to special receptors called androgen receptors. When testosterone binds to androgen receptors, the receptors move into the nucleus (the central part of the cell containing DNA and genetic material). They then alter the way different genes are switched on and off and converted into proteins (a process called ‘gene expression’).
Yes, women do produce testosterone, albeit in significantly lower amounts than men. The ovaries and adrenal glands are responsible for producing about 50% of testosterone in women.
The remaining 50% of testosterone is produced by peripheral tissues (e.g. the skin) from other androgen hormones (DHEA, DHEA-Sulfate and androstenodione) circulating in the bloodstream.
Like other steroid hormones, testosterone is made originally from cholesterol. There are several different pathways by which cholesterol is ultimately converted into testosterone. It all gets a bit complicated but, briefly, there are two pathways, one major pathway. The first stage in both pathways is the production of pregnenolone.
In the major pathway, pregnenolone is made into another androgen, DHEA. From there, DHEA is converted into another androgen, androstenodione, before finally being made into testosterone.
In a second, minor pathway, pregnenolone is converted into progesterone – a key female sex hormone (but also produced by men). Progesterone is then converted into androstenodione and then into testosterone.
It’s helpful to understand that these pathways are important not just for producing testosterone. Rather, many of the intermediary molecules in both pathways (e.g. DHEA, progesterone) are key hormones themselves, carrying out a range of essential functions. Many of the intermediary molecules are also subsequently converted into other hormones. For example, progesterone can get converted into the stress hormone, cortisol, or the hormone aldosterone (which we learned about in a previous blog).
Although testosterone is biologically active and has many direct effects in the body, it can also be converted into a much more potent form, dihydrotestosterone or DHT.
In fact, despite its levels being 10 times lower than that of testosterone, DHT is responsible for most of the effects of testosterone in the body.
Once testosterone travels to tissues such as the skin, liver, hair follicles and (in men) the prostate gland, it is converted by an enzyme called ‘5a-reductase’ into DHT. DHT then binds to androgen receptors, where it carries out the various biological processes outlined earlier.
Testosterone also gets converted into estradiol, an estrogen hormone.
Although estrogens are considered to be ‘female sex hormones’, they are produced and play key roles in both men and women. As with the formation of DHT (explained above), the conversion of testosterone into estradiol takes places in various peripheral tissues, including bone, fat (adipose tissue) and cells of the male reproductive tract.
When testosterone reaches these tissues, it is converted into estradiol by an enzyme called aromatase. This pathway for producing estrogens may be particularly important in post-menopausal women, as direct formation of estrogens by the ovaries starts to decline. It is also especially important for bone health, in both men and women, as estrogen helps with the laying down of new bone tissue.
As they are small, fat-soluble molecules which can easily enter cells, steroid hormones are typically transported in the bloodstream by special carrier proteins. The vast majority (roughly 98%) of testosterone is bound to one of two proteins in the plasma: sex-hormone binding globulin (SHBG) or albumin. The remaining 1-2% of testosterone is not bound to protein and is described as ‘free testosterone.’
When testosterone is bound to SHBG (and to a lesser extent albumin), it is not free to enter and bind to androgen receptors in cells. In other words, testosterone bound to SHBG is inactive. Only free testosterone is active.
Consequently, your levels of SHBG strongly influence the activity and effects of testosterone.
Sex hormone binding globulin (SHBG) is a protein that strongly binds testosterone, as well as DHT (dihydrotestosterone – the more potent form of testosterone) and estrogens (estradiol and estrone).
When these sex steroids are bound to SHBG, they are essentially inactive. As such, SHBG levels affect the activity and exposure of cells to various sex steroids.
More specifically, when SHBG levels are excessively low, tissues in the body have greater exposure to androgens (DHT and testosterone) and estrogens (estradiol and estrone). This may be problematic, particularly in women, where it can lead to irregular periods (oligomenorrhea), acne, excessive hair growth (hirsutism) and weight gain.
By contrast, when SHBG levels are high, more testosterone (and other sex steroids) are bound and therefore inactive. Consequently, there is less free, active testosterone and DHT to carry out various important functions (outlined earlier) in the body. This can have various negative effects in both men and women, including: reduced bone and muscle mass, lower libido, poor concentration and tiredness.
It isn’t just the quantity of SHBG that affects the activity and function of testosterone. Alterations to the structure of the SHBG protein (brought on by genetic changes) can cause it to bind testosterone and other hormones more strongly or weakly. This then also affects how much testosterone is active and inactive.
This is difficult to answer precisely as levels of testosterone vary widely depending on sex, age, individual and the time of day.
For adult men, a healthy level of testosterone is between 270 ng / dL and 1100 ng/dL.
For adult women, a healthy level of testosterone is between 15 ng / dL and 70 ng/dL.
Note that these figures refer to total testosterone levels i.e. they include inactive testosterone bound to SHBG as well as free testosterone. Therefore, it is possible to have ‘normal’ total testosterone levels but have symptoms of low testosterone due to high levels of SHBG and low levels of free testosterone.
Also bear in mind that a blood test is required to accurately measure testosterone levels. At FitnessGenes, we use your genetic and lifestyle data to make an indirect prediction of your testosterone levels.
In men, testosterone levels rapidly rise during adolescence and peak around age 20. They then remain relatively stable until around age 40. Afterwards they start to gradually decline by about 1% per year. By age 70, testosterone levels have dropped to 30% below peak levels.
This slow decline results from slightly reduced production of testosterone by the testes. Specifically, testosterone-producing Leydig cells in the testes become less responsive to LH (luteneizing hormone) secreted by the pituitary gland.
Despite this decline, testosterone levels remain in the ‘normal’ healthy range in most men well into old age.
Nevertheless, studies suggest that about 20% of men over 60, 30% over 70 and 50% of men over 80 years old have low testosterone levels.
In contrast to men, women experience much a less rapid rise in testosterone levels during adolescence. In women, as with men, levels of testosterone peak around age 20 and start to gradually slowly decline with age.
During the menopause, the production of various sex hormones by the ovaries starts to decline rapidly. While levels of estrogen and progesterone drop dramatically, testosterone levels only drop slightly. The adrenal glands also produce slightly less testosterone with age.
- Low testosterone and muscle mass
Testosterone stimulates the growth of muscle. There are various ways by which it does this. Studies suggest that testosterone encourages stem cells in your body to specialise and develop into skeletal muscle cells. Testosterone also enhances the process of muscle protein synthesis.
Owing to these effects, when levels of testosterone are low, people may experience a loss of muscle mass.
- Low testosterone and body composition
In addition to promoting muscle growth, testosterone stimulates the reduction of fat mass. There are several ways by which testosterone enhances fat loss. Testosterone inhibits uptake of lipids by adipocytes (fat cells) and also stimulates the breakdown of fats for energy (a process called lipolysis).
Conversely, low testosterone levels are associated with the deposition of fat, particularly around the abdominal area (a phenomenon called central adiposity) and surrounding internal organs (visceral adiposity).
Furthermore, fat (adipose) tissue can also lower the production of testosterone, by reducing the amount of GnRH (gonadotropin releasing hormone) secreted by the hypothalamus. GnRH normally triggers the pituitary gland to produce LH, which, in turn, triggers the testes and ovaries to produce testosterone.
- Low Testosterone and blood sugar control
Low testosterone is linked to poorer control of blood sugars. The exact mechanism by which low testosterone upsets blood sugar control remains to be fully understood. For instance, it’s unclear whether raised blood sugar levels associated with low testosterone are merely secondary to changes in body composition (lower muscle mass and higher fat mass).
Nevertheless, studies suggest that low testosterone is linked to a phenomenon called ‘insulin resistance.’ Insulin is the hormone that allows tissues in the body to take up glucose that is circulating in the bloodstream. When tissues become less sensitive and resistant to the effects of insulin, they are less able to take up and use glucose for energy. This leads to higher levels of glucose remaining within the bloodstream. High blood glucose levels can be damaging in the long term and increase the risk of conditions such as diabetes.
There are several gene variants that affect both your ability to produce testosterone and the amount of circulating free testosterone in your bloodstream.
With regards to the latter, variants of your SHBG gene are particularly important.
As explained earlier, the SHBG (Sex Hormone Binding Globulin) protein binds to testosterone (and DHT), thereby inactivating these hormones. In simple scenarios, higher levels of circulating SHBG may lead to lower amounts of free, active testosterone. Conversely, lower levels of SHBG may lead to high amounts of free testosterone.
Some common mutations (or SNPs – Single Nucleotide Polymorphisms) of the SHBG gene affect your circulating levels of SHBG protein and thereby your free testosterone levels.
Other SNPs of the SHBG gene affect how strongly the SHBG protein binds to testosterone. If SHBG binds to testosterone with higher affinity, less free testosterone is available to have effects in the body.
Note that the SHBG protein also binds to other sex hormones, so your levels of hormones other than testosterone (e.g. estrogens) are also affected by variants of the SHBG gene.
Of course, genes aren’t the whole picture. Your current body composition strongly influences your current levels of testosterone. Similarly, environmental/ lifestyle factors such as your diet and exercise patterns also significantly impact testosterone production and activity.
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