Encyclopedia
Testosterone is a
steroid hormone from the androgen group. Testosterone is primarily secreted in the
testes of males and the
ovaries of females although small amounts are secreted by the
adrenal glands. It is the principal
male sex hormone and an
anabolic steroid. In both males and females, it plays key roles in health and well-being. Examples include enhanced libido, energy, immune function, and protection against osteoporosis. On average, the adult male body produces about twenty times the amount of testosterone an adult female's body does.
Sources of testosterone
Like other steroid hormones, testosterone is derived from
cholesterol. The largest amounts of testosterone are produced by the
testes in men, but it is also synthesized in smaller quantities in women by the
thecal cells of the
ovaries, by the
placenta, as well as by the zona reticularis of the
adrenal cortex in both sexes.
In the testes, testosterone is produced by the Leydig cells. The male generative glands also contain Sertoli cells which require testosterone for spermatogenesis. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein,
sex hormone binding globulin .
Some drugs have the side-effect of elevating testosterone levels, such as
finasteride which prevents testosterone from burning into DHT thereby raising the level of testosterone in the body.
Mechanism of effects
The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor , and by conversion to
estradiol and activation of certain
estrogen receptors.
Free testosterone is transported into the
cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5a-
dihydrotestosterone by the cytoplasmic enzyme 5a-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. 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 , 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 large 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 maturation 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 . 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.
Effects of testosterone on humans
In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone effects can be classified as
virilizing and
anabolic effects, although the distinction is somewhat artificial, as many of the effects can be considered both. Anabolic effects include growth of muscle mass and strength, increased bone density and strength, and stimulation of linear growth and bone maturation.
Virilizing effects include maturation of the sex organs, particularly the
penis and the formation of the
scrotum in fetuses, and after birth a deepening of the voice, growth of the
beard and axillary hair. Many of these fall into the category of male
secondary sex characteristics.
Testosterone effects can also be classified by the age of usual occurrence. For postnatal effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone.
Most of the
prenatal androgen effects occur between 7 and 12 weeks of gestation.
- Genital virilization
- Development of prostate and seminal vesicles
Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4-6 months of age. The function of this rise in humans is unknown. It has been speculated that "brain masculinization" is occurring since no significant changes have been identified in other parts of the body.
Early postnatal effects are the first visible effects of rising androgen levels in childhood, and occur in both boys and girls in puberty.
- Adult-type body odour
- Increased oiliness of skin and hair, acne
- Pubarche
- Axillary hair
- Growth spurt, accelerated bone maturation
- Fine upper lip and sideburn hair
Advanced postnatal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males these are normal late pubertal effects, and only occur in women after prolonged periods of excessive levels of free testosterone in the blood.
- Phallic enlargement
- Increased libido and erection frequency
- Pubic hair extends to thighs and up toward umbilicus
- Facial hair
- Chest hair, periareolar hair, perianal hair
- Subcutaneous fat in face decreases
- Increased muscle strength and mass
- Deepening of voice
- Growth of the adam's apple
- Growth of spermatogenic tissue in testes, male fertility
- Growth of jaw, brow, chin, nose, and remodeling of facial bone contours
- Shoulders widen and rib cage expands
- Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women.
Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels decline in the later decades of adult life.
- Maintenance of muscle mass and strength
- Maintenance of bone density and strength
- Libido and erection frequency
- Mental and physical energy
Testosterone in athletes
Testosterone may be administered to an athlete in order to improve performance, and is considered to be a form of doping in most sports. There are several application methods for testosterone, including intramuscular injections, transdermal gels and patches, and implantable pellets.
Anabolic steroids have also been taken to enhance muscle development, strength, or endurance. After a series of scandals and publicity in the 1980s , prohibitions of anabolic steroid use were renewed or strengthened by many sports organizations. Testosterone and other anabolic steroids were designated a "controlled substance" by the United States Congress in 1990, with the Anabolic Steroid Control Act.
Therapeutic use of testosterone
Testosterone was first isolated from a bull in 1935. There have been many pharmaceutical forms over the years. Forms of testosterone for human administration currently available in North America include injectable , oral , buccal , transdermal skin patches, and transdermal creams or gels and . In the pipeline are a "roll on" delivery method and a nasal spray.
The original and primary use of testosterone is for the treatment of males who have too little or no natural endogenous testosterone production; males with hypogonadism. Appropriate use for this purpose is legitimate hormone replacement therapy, which maintains serum testosterone levels in the normal range.
However, over the years, as with every hormone, testosterone or other anabolic steroids has also been given for many other conditions and purposes besides replacement, with variable success but higher rates of side effects or problems. Examples include infertility, lack of libido or erectile dysfunction, osteoporosis, penile enlargement, height growth,
bone marrow stimulation and reversal of anemia, and even appetite stimulation. By the late 1940s testosterone was being touted as an anti-aging wonder drug .
To take advantage of its virilizing effects, testosterone is often administered to transmen as part of the hormone replacement therapy, with a "target level" of the normal male testosterone level. And like-wise, transwomen are sometimes prescribed drugs [anti-androgens] to decrease the level of testosterone in the body and allow for the effects of estrogen to develop.
There is a myth that exogenous testosterone can more or less definitively be used for male birth control. However, the vast majority of physicians will agree that to prescribe exogenous testosterone for this purpose is inappropriate. But perhaps more importantly, many men of first hand found this myth to be untrue or at least, unreliable. This is especially true when exogenous testosterone is used in conjunction with hCG.
Exogenous testosterone supplementation comes with a number of health risks. Fluoxymesterone and methyltestosterone are synthetic derivatives of testosterone. In 2006 it was reported that women taking Estratest, a combination pill including estrogen and methyltestosterone, were at considerably heightened risk of breast cancer.
The "testosterone deficiency" of aging and the andropause controversy
Testosterone levels decline gradually with age in men. The clinical significance of this decrease is debated . There is disagreement about if and when to treat aging men with testosterone replacement therapy. The American Society of Andrology's position is that testosterone therapy "is indicated when both clinical symptoms and signs suggestive of androgen deficiency and decreased testosterone levels are present". The American Association of Clinical Endocrinologists says "Hypogonadism is defined as a free testosterone level that is below the lower limit of normal for young adult control subjects. Previously, age-related decreases in free testosterone were once accepted as normal. Currently, they are not considered normal....Patients with low-normal to subnormal range testosterone levels warrant a clinical trial of testosterone."
There isn't total agreement on the threshold of testosterone value below which a man would be considered hypogonadal. Testosterone can be measured as "free" or more commonly, "total" . In the United States, male total testosterone levels below 200 to 300 ng/dl from a morning sample are generally considered low. However these numbers are typically not age-adjusted, but based on an average of a test group which includes elderly males with low testosterone levels. Therefore a value of 300 ng/dl might be normal for a 90 year old male, but not normal for a 30 year old. Identification of inadequate testosterone in an aging male by symptoms alone can be difficult. The signs and symptoms are non-specific, and might be confused with normal aging characteristics, such as loss of muscle mass and bone density, decreased physical endurance, decreased memory ability and loss of libido.
Replacement therapy can take the form of injectable depots, transdermal patches and gels, subcutaneous pellets and oral therapy. Adverse effects of testosterone supplementation include minor side effects such as acne and oily skin, and more significant complications such as increased
hematocrit, exacerbation of
sleep apnea and acceleration of pre-existing
prostate cancer growth. Exogenous testosterone also causes suppression of
spermatogenesis and can lead to infertility. It is recommended that physicians screen for prostate cancer with a digital rectal exam and PSA level prior to initiating therapy, and monitor hematocrit and PSA levels closely during therapy.
Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking. Many caution against embracing testosterone replacement therapy because of lessons from the female hormone replacement therapy trials, where initially promising results were later refuted by larger studies.
Synthesis
Testosterone is synthesized from
pregnenolone, which is the precursor of all
steroid hormones and is made from
cholesterol by a series of enzymatic reactions. two pathways are possible, In the delta-5 pathway, pregnenolone is converted to
DHEA to
androstenedione.
In the delta-4 pathway there is hydroxylation of C-17 of
progesterone, to yield 17a-hydroxyprogesterone. The side chain is then cleaved to form
androstenedione. Androstenedione is the immediate precursor to testosterone.
The
keto group on C-17 is reduced to an
alcohol to yield testosterone. Testosterone is a potential precursor of
estradiol.
Zinc supplementation is known to result in increased levels of testosterone synthesis, especially in those who are zinc deficient. Zinc is critical to the proper function of steroid receptors and plays a vital role as a cofactor to many
enzymes which is the likely mechanim for its effect on testosterone synthesis.
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