Testosterone
Testosterone is the primary male sex hormone and androgen in males.[3] In humans, testosterone plays a key role in the development of male reproductive tissues such as testicles and prostate, as well as promoting secondary sexual characteristics such as increased muscle and bone mass, and the growth of body hair. It is associated with increased aggression, sex drive, dominance, courtship display, and a wide range of behavioral characteristics.[4] In addition, testosterone in both sexes is involved in health and well-being, where it has a significant effect on overall mood, cognition, social and sexual behavior, metabolism and energy output, the cardiovascular system, and in the prevention of osteoporosis.[5][6] Insufficient levels of testosterone in men may lead to abnormalities including frailty, accumulation of adipose fat tissue within the body, anxiety and depression, sexual performance issues, and bone loss.
This article is about testosterone as a hormone. For its use as a medication, see Testosterone (medication). For other uses, see Testosterone (disambiguation).
Excessive levels of testosterone in men may be associated with hyperandrogenism, higher risk of heart failure, increased mortality in men with prostate cancer,[7] male pattern baldness.
Testosterone is a steroid from the androstane class containing a ketone and a hydroxyl group at positions three and seventeen respectively. It is biosynthesized in several steps from cholesterol and is converted in the liver to inactive metabolites.[8] It exerts its action through binding to and activation of the androgen receptor.[8] In humans and most other vertebrates, testosterone is secreted primarily by the testicles of males and, to a lesser extent, the ovaries of females. On average, in adult males, levels of testosterone are about seven to eight times as great as in adult females.[9] As the metabolism of testosterone in males is more pronounced, the daily production is about 20 times greater in men.[10][11] Females are also more sensitive to the hormone.[12]
In addition to its role as a natural hormone, testosterone is used as a medication to treat hypogonadism and breast cancer.[13] Since testosterone levels decrease as men age, testosterone is sometimes used in older men to counteract this deficiency. It is also used illicitly to enhance physique and performance, for instance in athletes.[14] The World Anti-Doping Agency lists it as S1 Anabolic agent substance "prohibited at all times".[15]
Biological effects[edit]
Effects on physiological development[edit]
In general, androgens such as testosterone promote protein synthesis and thus growth of tissues with androgen receptors.[16] Testosterone can be described as having anabolic and androgenic (virilising) effects, though these categorical descriptions are somewhat arbitrary, as there is a great deal of mutual overlap between them.[17] The relative potency of these effects can depend on various factors and is a topic of ongoing research.[18][19] Testosterone can either directly exert effects on target tissues or be metabolized by 5α-reductase into dihydrotestosterone (DHT) or aromatized to estradiol (E2).[18] Both testosterone and DHT bind to an androgen receptor; however, DHT has a stronger binding affinity than testosterone and may have more androgenic effect in certain tissues at lower levels.[18]
Biological activity[edit]
Free testosterone[edit]
Lipophilic hormones (soluble in lipids but not in water), such as steroid hormones, including testosterone, are transported in water-based blood plasma through specific and non-specific proteins. Specific proteins include sex hormone-binding globulin (SHBG), which binds testosterone, dihydrotestosterone, estradiol, and other sex steroids. Non-specific binding proteins include albumin. The part of the total hormone concentration that is not bound to its respective specific carrier protein is the free part. As a result, testosterone which is not bound to SHBG is called free testosterone. Only the free amount of testosterone can bind to an androgenic receptor, which means it has biological activity.[134] While a significant portion of testosterone is bound to SHBG, a small fraction of testosterone (1%-2%)[135] is bound to albumin and the binding of testosterone to albumin is weak and can be reversed easily;[136][137] as such, both albumin-bound and unbound testosterone are considered to be bioavailable testosterone.[136][137] This binding plays an important role in regulating the transport, tissue delivery, bioactivity, and metabolism of testosterone.[137][136]At the tissue level, testosterone dissociates from albumin and quickly diffuses into the tissues. The percentage of testosterone bound to SHBG is lower in men than in women. Both the free fraction and the one bound to albumin are available at the tissue level (their sum constitutes the bioavailable testosterone), while SHBG effectively and irreversibly inhibits the action of testosterone.[135] The relationship between sex steroids and SHBG in physiological and pathological conditions is complex, as various factors may influence the levels of plasma SHBG, affecting bioavailability of testosterone.[138][139][140]
Steroid hormone activity[edit]
The effects of testosterone in humans and other vertebrates occur by way of multiple mechanisms: by activation of the androgen receptor (directly or as dihydrotestosterone), and by conversion to estradiol and activation of certain estrogen receptors.[141][142] Androgens such as testosterone have also been found to bind to and activate membrane androgen receptors.[143][144][145]
Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (5α-DHT) by the cytoplasmic enzyme 5α-reductase. 5α-DHT binds to the same androgen receptor even more strongly than testosterone, so that its androgenic potency is about 5 times that of T.[146] The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects.
Androgen receptors occur in many different vertebrate body system tissues, and both males and females respond similarly to similar levels. Greatly differing amounts of testosterone prenatally, at puberty, and throughout life account for a share of biological differences between males and females.
The bones and the brain are two important tissues in humans where the primary effect of testosterone is by way of aromatization to estradiol. In the bones, estradiol accelerates ossification of cartilage into bone, leading to closure of the epiphyses and conclusion of growth. In the central nervous system, testosterone is aromatized to estradiol. Estradiol rather than testosterone serves as the most important feedback signal to the hypothalamus (especially affecting LH secretion).[147] In many mammals, prenatal or perinatal "masculinization" of the sexually dimorphic areas of the brain by estradiol derived from testosterone programs later male sexual behavior.[148]
Neurosteroid activity[edit]
Testosterone, via its active metabolite 3α-androstanediol, is a potent positive allosteric modulator of the GABAA receptor.[149]
Testosterone has been found to act as an antagonist of the TrkA and p75NTR, receptors for the neurotrophin nerve growth factor (NGF), with high affinity (around 5 nM).[150][151][152] In contrast to testosterone, DHEA and DHEA sulfate have been found to act as high-affinity agonists of these receptors.[150][151][152]
Testosterone is an antagonist of the sigma-1 receptor (Ki = 1,014 or 201 nM).[153] However, the concentrations of testosterone required for binding the receptor are far above even total circulating concentrations of testosterone in adult males (which range between 10 and 35 nM).[154]
Dimeric sex hormone-binding globulin with its testosterone ligands
Two methods for determining the concentration of bioavailable testosterone
In measurements of testosterone in blood samples, different assay techniques can yield different results.[209][210] Immunofluorescence assays exhibit considerable variability in quantifying testosterone concentrations in blood samples due to the cross-reaction of structurally similar steroids, leading to overestimating the results. In contrast, the liquid chromatography/tandem mass spectrometry method is more desirable: it offers superior specificity and precision, making it a more suitable choice for this application.[211]
Testosterone's bioavailable concentration is commonly determined using the Vermeulen calculation or more precisely using the modified Vermeulen method,[212][213] which considers the dimeric form of sex hormone-binding globulin.[214]
Both methods use chemical equilibrium to derive the concentration of bioavailable testosterone: in circulation, testosterone has two major binding partners, albumin (weakly bound) and sex hormone-binding globulin (strongly bound). These methods are described in detail in the accompanying figure.
Distribution[edit]
Testosterone has been detected at variably higher and lower levels among men of various nations and from various backgrounds, explanations for the causes of this have been relatively diverse.[215][216]
People from nations of the Eurasian Steppe and Central Asia, such as Mongolia, Kyrgyzstan and Uzbekistan, have consistently been detected to have had significantly elevated levels of Testosterone,[217] while people from Central European and Baltic nations such as the Czech Republic, Slovakia, Latvia and Estonia have been found to have had significantly decreased levels of Testosterone.[218]
The region with the highest-ever tested levels of Testosterone is Chita, Russia, the people group with the highest ever tested levels of Testosterone were the Yakuts.[219]
Other species[edit]
Testosterone is observed in most vertebrates. Testosterone and the classical nuclear androgen receptor first appeared in gnathostomes (jawed vertebrates).[233] Agnathans (jawless vertebrates) such as lampreys do not produce testosterone but instead use androstenedione as a male sex hormone.[234] Fish make a slightly different form called 11-ketotestosterone.[235] Its counterpart in insects is ecdysone.[236] The presence of these ubiquitous steroids in a wide range of animals suggest that sex hormones have an ancient evolutionary history.[237]