Testosterone
Encyclopedia
Testosterone is a steroid hormone
from the androgen
group and is found in mammals, reptiles, birds, and other vertebrate
s. In mammal
s, testosterone is primarily secreted in the testes of male
s and the ovaries of female
s, although small amounts are also secreted by the adrenal gland
s. It is the principal male
sex hormone
and an anabolic steroid
.
In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate
as well as promoting secondary sexual characteristics such as increased muscle
, bone
mass, and the growth of body hair
. In addition, testosterone is essential for health and well-being as well as the prevention of osteoporosis
.
On average, an adult human
male body produces about ten times more testosterone than an adult human female body, but females are more sensitive to the hormone.
Testosterone is observed in most vertebrates. Fish
make a slightly different form called 11-ketotestosterone
. Its counterpart in insects is ecdysone
. These ubiquitous steroids suggest that sex hormones have an ancient evolutionary history.
and anabolic
, although the distinction is somewhat artificial, as many of the effects can be considered both. Testosterone is anabolic, meaning it builds up bone and muscle mass.
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.
During the 2nd trimester androgen level is associated with Gender identity
This period affects the femininization or masculinization of the fetus and is a better predictor of an adult's femininity or masculinity than an adult's own levels. In other words, an adult's own testosterone level influences behavior less than the mother's during pregnancy.
" is occurring since no significant changes have been identified in other parts of the body. Surprisingly, the male brain is masculinized by testosterone being aromatized into estrogen, which crosses the blood-brain barrier
and enters the male brain, whereas female fetuses have alpha-fetoprotein
which binds up the estrogen so that female brains are not affected.
androgen levels at the end of childhood, occurring in both boys and girls.
aromatase
converts testosterone into estradiol
that is responsible for masculinization of the brain in male mice. In humans, masculinization of the fetal brain appears, by observation of gender preference in patients with congenital diseases of androgen formation or androgen receptor function, to be associated with functional androgen receptors.
There are some differences between a male and female brain (possibly the result of different testosterone levels), one of them being size: the male human brain is, on average, larger. In a Danish study from 2003, men were found to have a total myelinated fiber length of 176,000 km at the age of 20, whereas in women the total length was 149,000 km.
A study conducted in 1996 found no immediate short term effects on mood or behavior from the administration of supraphysiologic doses of testosterone for 10 weeks on 43 healthy men. Another study found a correlation between testosterone and risk tolerance in career choice among women.
Literature suggests that attention, memory, and spatial ability are key cognitive functions affected by testosterone in humans. Preliminary evidence suggests that low testosterone levels may be a risk factor for cognitive decline and possibly for dementia
of the Alzheimer’s type, a key argument in life extension
medicine for the use of testosterone in anti-aging therapies. Much of the literature, however, suggests a curvilinear or even quadratic relationship between spatial performance and circulating testosterone, where both hypo- and hypersecretion (deficient- and excessive-secretion) of circulating androgens have negative effects on cognition and cognitively modulated aggressivity, as detailed above.
Contrary to what has been postulated in outdated studies and by certain sections of the media, aggressive behaviour is not typically seen in hypogonadal men who have their testosterone replaced adequately to the eugonadal/normal range. In fact, aggressive behaviour has been associated with hypogonadism and low testosterone levels and it would seem as though supraphysiological and low levels of testosterone and hypogonadism
cause mood disorder
s and aggressive
behaviour, with eugondal/normal testosterone levels being important for mental well-being. Testosterone depletion is a normal consequence of aging in men. One possible consequence of this could be an increased risk for the development of Alzheimer’s disease.
is known to correlate with aggression in male mice.
. Differences in sex hormones including testosterone have been suggested as an explanation for these differences. A 2009 study found ethnical differences between blacks and whites in the testosterone to sex hormone binding globulin
ratio in blood from the umbilical cord
in infants.
. Appropriate use for this purpose is legitimate hormone replacement therapy (testosterone replacement therapy [TRT]), 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 varying success but higher rates of side effects or problems. Examples include reducing infertility
, correcting lack of libido or erectile dysfunction, correcting osteoporosis
, encouraging penile enlargement
, encouraging height growth, encouraging bone marrow
stimulation and reversing the effects of anemia
, and even appetite stimulation. By the late 1940s testosterone was being touted as an anti-aging wonder drug (e.g., see Paul de Kruif
's The Male Hormone). Decline of testosterone production with age has led to interest in androgen replacement therapy
.
To take advantage of its virilizing effects, testosterone is often administered to transsexual men as part of the hormone replacement therapy
, with a "target level" of the normal male testosterone level. Like-wise, transsexual women are sometimes prescribed anti-androgens
to decrease the level of testosterone in the body and allow for the effects of estrogen to develop.
Testosterone patches are effective at treating low libido in post-menopausal women. Low libido may also occur as a symptom or outcome of hormonal contraceptive use. Women may also use testosterone therapies to treat or prevent loss of bone density, muscle mass and to treat certain kinds of depression and low energy state. Women on testosterone therapies may experience an increase in weight without an increase in body fat due to changes in bone and muscle density. Most undesired effects of testosterone therapy in women may be controlled by hair-reduction strategies, acne prevention, etc. There is a theoretical risk that testosterone therapy may increase the risk of breast or gynaecological cancers, and further research is needed to define any such risks more clearly.
). There is disagreement about when to treat aging men with testosterone replacement therapy. The American Society of Andrology's position is that "testosterone replacement therapy in aging men 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 is not total agreement on the threshold of testosterone value below which a man would be considered hypogonadal. (Currently there are no standards as to when to treat women.) Testosterone can be measured as "free" (that is, bioavailable and unbound) or more commonly, "total" (including the percentage which is chemically bound and unavailable). In the United States, male total testosterone levels below 300 ng/dL from a morning serum sample are generally considered low. Identification of inadequate testosterone in an aging male by symptoms alone can be difficult.
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
which can require venipuncture
in order to treat, exacerbation of sleep apnea
and acceleration of pre-existing prostate cancer
growth in individuals who have undergone androgen deprivation. Another adverse effect may be significant hair loss and/or thinning of the hair. This may be prevented with Propecia (Finasteride), which blocks DHT (a byproduct of testosterone in the body), during treatment. 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 (prostate specific antigen
) level before starting therapy, and monitor hematocrit and PSA levels closely during therapy.
. A small trial in 2005 showed mixed results in using testosterone to combat the effects of aging.
Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking.
and methyltestosterone
are synthetic derivatives of testosterone. Methyltestosterone and Fluoxymesterone are no longer prescribed by physicians given their poor safety record, and testosterone replacement in men does have a very good safety record as evidenced by over sixty years of medical use in hypogonadal men.
A 2006 article in Official Journal of the American Urological Association - The Journal of Urology
pointed out that: Prostate cancer may become clinically apparent within months to a few years after the initiation of testosterone treatment. [...] Physicians prescribing testosterone supplementation and patients receiving it should be cognizant of this risk, and serum PSA testing and digital rectal examination should be performed frequently during treatment.
in most sports. There are several application methods for testosterone, including intramuscular injection
s, transdermal gels and patches
, and implantable pellets.
Anabolic steroids (including testosterone) have also been taken to enhance muscle development, strength, or endurance. They do so directly by increasing the muscles' protein synthesis. As a result, muscle fibers become larger and repair faster than the average person's.
After a series of scandals and publicity in the 1980s (such as Ben Johnson's improved performance at the 1988 Summer Olympics
), prohibition
s 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. The use is seen as being a seriously problematic issue in modern sport, particularly given the lengths to which athletes and professional laboratories go to in trying to conceal such abuse from sports regulators. Steroid abuse once again came into the spotlight recently as a result of the Chris Benoit
double murder-suicide in 2007, and the media frenzy surrounding it - however, there has been no evidence indicating steroid use as a contributing factor.
. These include the testosterone/epitestosterone
ratio (normally less than 6), the testosterone/luteinizing hormone ratio and the carbon-13
/ carbon-12
ratio (pharmaceutical testosterone contains less carbon-13 than endogenous testosterone). In some testing programs, an individual's own historical results may serve as a reference interval for interpretation of a suspicious finding. Another approach being investigated is the detection of the administered form of testosterone, usually an ester, in hair.
, transdermal skin patches, transdermal creams, gels, and implantable pellets. Roll-on methods and nasal sprays are currently under development.
Like other steroid
hormones, testosterone is derived from cholesterol
(see figure to the right). The first step in the biosynthesis
involves the oxidative cleavage of the sidechain of cholesterol by CYP11A
, a mitochondrial
cytochrome P450 oxidase with the loss of six carbon atoms to give pregnenolone
. In the next step, two additional carbon atoms are removed by the CYP17A enzyme in the endoplasmic reticulum
to yield a variety of C19 steroids. In addition, the 3-hydroxyl group is oxidized by 3-β-HSD
to produce androstenedione
. In the final and rate limiting step, the C-17 keto group androstenedione is reduced by 17-β hydroxysteroid dehydrogenase
to yield testosterone.
The largest amounts of testosterone (>95%) are produced by the testes in men. It is also synthesized in far 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 cell
s. The male generative glands also contain Sertoli cell
s 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
(SHBG).
(LH) and follicle stimulating hormone (FSH). In addition, the amount of testosterone produced by existing Leydig cells is under the control of LH which regulates the expression of 17-β hydroxysteroid dehydrogenase.
The amount of testosterone synthesized is regulated by the hypothalamic-pituitary-testicular axis
(see figure to the right). When testosterone levels are low, gonadotropin-releasing hormone (GnRH
) is released by the hypothalamus
which in turn stimulates the pituitary gland
to release FSH and LH. These later two hormones stimulate the testis to synthesize testosterone. Finally increasing levels of testosterone through a negative feedback
loop act on the hypothalamus and pituitary to inhibit the release of GnRH and FSH/LH respectively.
Environmental factors affecting testosterone levels include:
(DHT) by the cytochrome P450 enzyme 5α-reductase
, an enzyme highly expressed in male accessory sex organs and hair follicles. Approximately 0.3% of testosterone is converted into estradiol by aromatase
(CYP19A1) an enzyme expressed in the brain, liver, and adipose tissues.
DHT is a more potent form of testosterone while estradiol has completely different activities (feminization) compared to testosterone (masculinization). Finally testosterone and DHT may be deactivated or cleared by enzymes that hydroxylate at the 6, 7, 15 or 16 positions.
(directly or as DHT), and by conversion to estradiol
and activation of certain estrogen receptor
s.
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
(DHT) by the cytoplasmic enzyme 5-alpha reductase
. DHT binds to the same androgen receptor even more strongly than testosterone, so that its androgenic potency is about 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 element
s (HREs), and influence transcriptional activity of certain gene
s, 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 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 (especially affecting LH
secretion). In many mammal
s, prenatal or perinatal "masculinization" of the sexually dimorphic
areas of the brain by estradiol derived from testosterone programs later male sexual behavior.
The human hormone testosterone is produced in greater amounts by males, and less by females. The human hormone estrogen
is produced in greater amounts by females, and less by males. Testosterone causes the appearance of masculine traits (i.e., deepening voice, pubic and facial hairs, muscular build, etc.) Like men, women rely on testosterone to maintain libido, bone density and muscle mass throughout their lives. In men, inappropriately high levels of estrogens lower testosterone, decrease muscle mass, stunt growth in teenagers, introduce gynecomastia
, increase feminine characteristics, and decrease susceptibility to prostate cancer, reduces libido and causes erectile dysfunction
and can cause excessive sweating and hot flushes . However, an appropriate amount of estrogens is required in the male in order to ensure well-being, bone density, libido, erectile function, etc.
and metabolic half life
relative to testosterone. Many of these analogs have an alkyl group introduced at the C-17 position in order to prevent conjugation and hence improve oral bioavailability. These are the so-called “17-aa” (17-alkyl androgen) family of androgens such as fluoxymesterone
and methyltestosterone
.
s such as finasteride
inhibits the conversion of testosterone into dihydrotestosterone
(DHT), a metabolite which is more potent than testosterone. These 5-alpha-reductase inhibitors have been used to treat various conditions associated with androgens, such as androgenetic alopecia
(male-pattern baldness), hirsutism
, benign prostatic hyperplasia
(BPH), and prostate cancer
. Alternatively GnRH antagonists
bind to GnRH receptors
in the pituitary gland
, blocking the release of luteinising hormone (LH) and follicle-stimulating hormone
(FSH) from the pituitary. In men, the reduction in LH subsequently leads to rapid suppression of testosterone release from the testes. GnRH antagonists have been used for the treatment of prostate cancer.
" in men, as a comparison to the decline in estrogen
that comes with menopause
in women.
(1803–1861). Research on the action of testosterone received a brief boost in 1889, when the Harvard professor Charles-Édouard Brown-Séquard
(1817–1894), then in Paris, self-injected subcutaneously a “rejuvenating elixir” consisting of an extract of dog and guinea pig testicle. He reported in The Lancet that his vigor and feeling of well-being were markedly restored but, predictably, the effects were transient (and likely based on a placebo effect), and Brown-Séquard’s hopes for the compound were dashed. Suffering the ridicule of his colleagues, his work on the mechanisms and effects of androgens in human beings was abandoned by Brown-Séquard and succeeding generations of biochemists for nearly 40 years.
The trail remained cold until the University of Chicago’s Professor of Physiologic Chemistry, Fred C. Koch, established easy access to a large source of bovine testicles—the Chicago stockyards—and to students willing to endure the ceaseless toil of extracting their isolates. In 1927, Koch and his student, Lemuel McGee, derived 20 mg of a substance from a supply of 40 pounds of bovine testicles that, when administered to castrated roosters, pigs and rats, remasculinized them. The group of Ernst Laqueur at the University of Amsterdam purified testosterone from bovine testicles in a similar manner in 1934, but isolation of the hormone from animal tissues in amounts permitting serious study in humans was not feasible until three European pharmaceutical giants—Schering
(Berlin, Germany), Organon
(Oss, Netherlands) and Ciba (Basel, Switzerland)—began full-scale steroid research and development programs in the 1930s.
The Organon group in the Netherlands were the first to isolate the hormone, identified in a May 1935 paper "On Crystalline Male Hormone from Testicles (Testosterone)". They named the hormone testosterone, from the stems of testicle and sterol
, and the suffix
of ketone
. The structure was worked out by Schering’s Adolf Butenandt
.
The chemical synthesis
of testosterone from cholesterol was achieved in August that year by Butenandt and Hanisch. Only a week later, the Ciba group in Zurich, Leopold Ruzicka (1887–1976) and A. Wettstein, published their synthesis of testosterone. These independent partial syntheses of testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939 Nobel Prize in Chemistry
. Testosterone was identified as 17β-hydroxyandrost-4-en-3-one (C19H28O2), a solid polycyclic alcohol with a hydroxyl group at the 17th carbon atom. This also made it obvious that additional modifications on the synthesized testosterone could be made, i.e., esterification and alkylation.
The partial synthesis in the 1930s of abundant, potent testosterone esters permitted the characterization of the hormone’s effects, so that Kochakian and Murlin (1936) were able to show that testosterone raised nitrogen retention (a mechanism central to anabolism) in the dog, after which Allan Kenyon’s group was able to demonstrate both anabolic and androgenic effects of testosterone propionate in eunuchoidal men, boys, and women. The period of the early 1930s to the 1950s has been called "The Golden Age of Steroid Chemistry", and work during this period progressed quickly. Research in this golden age proved that this newly synthesized compound—testosterone—or rather family of compounds (for many derivatives were developed from 1940 to 1960), was a potent multiplier of muscle, strength, and well-being.
Steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens...
from the androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
group and is found in mammals, reptiles, birds, and other vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s. In mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s, testosterone is primarily secreted in the testes of male
Male
Male refers to the biological sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilization...
s and the ovaries of female
Female
Female is the sex of an organism, or a part of an organism, which produces non-mobile ova .- Defining characteristics :The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male...
s, although small amounts are also secreted by the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s. It is the principal male
Male
Male refers to the biological sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilization...
sex hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
and an anabolic steroid
Anabolic steroid
Anabolic steroids, technically known as anabolic-androgen steroids or colloquially simply as "steroids", are drugs that mimic the effects of testosterone and dihydrotestosterone in the body. They increase protein synthesis within cells, which results in the buildup of cellular tissue ,...
.
In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
as well as promoting secondary sexual characteristics such as increased muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
, bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
mass, and the growth of body hair
Androgenic hair
Androgenic hair, colloquially body hair, is the terminal hair that develops on the body during and after puberty. It is differentiated from the head hair and less visible vellus hair, which are much finer and lighter in color. The growth of androgenic hair is related to the level of androgens in...
. In addition, testosterone is essential for health and well-being as well as the prevention of osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
.
On average, an adult human
Human
Humans are the only living species in the Homo genus...
male body produces about ten times more testosterone than an adult human female body, but females are more sensitive to the hormone.
Testosterone is observed in most vertebrates. Fish
Fish
Fish are a paraphyletic group of organisms that consist of all gill-bearing aquatic vertebrate animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish, as well as various extinct related groups...
make a slightly different form called 11-ketotestosterone
11-Ketotestosterone
11-Ketotestosterone is an oxidized form of testosterone that contains a keto group at position-11. It is related to adrenosterone, an androgen found in trace quantities in humans. In fish, 11-ketotestosterone functions as the endogenous androgenic sex hormone....
. Its counterpart in insects is ecdysone
Ecdysone
Ecdysone is a steroidal prohormone of the major insect molting hormone 20-hydroxyecdysone, which is secreted from the prothoracic glands. Insect molting hormones are generally called ecdysteroids. Ecdysteroids act as moulting hormones of arthropods but also occur in other related phyla where they...
. These ubiquitous steroids suggest that sex hormones have an ancient evolutionary history.
Physiological effects
In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone effects can be classified as virilizingVirilization
In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens...
and anabolic
Anabolism
Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy. One way of categorizing metabolic processes, whether at the cellular, organ or organism level is as 'anabolic' or as 'catabolic', which is the opposite...
, although the distinction is somewhat artificial, as many of the effects can be considered both. Testosterone is anabolic, meaning it builds up bone and muscle mass.
- Anabolic effects include growth of muscle mass and strength, increased bone densityBone densityBone density is a medical term normally referring to the amount of mineral matter per square centimeter of bones. Bone density is used in clinical medicine as an indirect indicator of osteoporosis and fracture risk.This medical bone density is not the true physical "density" of the bone, which...
and strength, and stimulation of linear growth and bone maturation. - Androgenic effects include maturationMaturationMaturation could refer to any of the following:* Fetal development* Developmental biology* Emotional development* Or physical maturation of any biological life form - see individual articles for maturation of different life forms....
of the sex organs, particularly the penisPenisThe penis is a biological feature of male animals including both vertebrates and invertebrates...
and the formation of the scrotumScrotumIn some male mammals the scrotum is a dual-chambered protuberance of skin and muscle containing the testicles and divided by a septum. It is an extension of the perineum, and is located between the penis and anus. In humans and some other mammals, the base of the scrotum becomes covered with curly...
in the fetus, and after birth (usually at pubertyPubertyPuberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
) a deepening of the voice, growth of the beardBeardA beard is the collection of hair that grows on the chin, cheeks and neck of human beings. Usually, only pubescent or adult males are able to grow beards. However, women with hirsutism may develop a 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
Postnatal
Postnatal is the period beginning immediately after the birth of a child and extending for about six weeks. Another term would be postpartum period, as it refers to the mother...
effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone.
Prenatal
the prenatal androgen effects occur during two different stages. Between 4 and 6 weeks of the gestation.- Genital virilization (midline fusion, phallicPhallusA phallus is an erect penis, a penis-shaped object such as a dildo, or a mimetic image of an erect penis. Any object that symbolically resembles a penis may also be referred to as a phallus; however, such objects are more often referred to as being phallic...
urethraUrethraIn anatomy, the urethra is a tube that connects the urinary bladder to the genitals for the removal of fluids out of the body. In males, the urethra travels through the penis, and carries semen as well as urine...
, scrotal thinning and rugation, phallic enlargement); although the role of testosterone is far smaller than that of DihydrotestosteroneDihydrotestosteroneDihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
. - Development of prostateProstateThe prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
and seminal vesicleSeminal vesicleThe seminal vesicles or vesicular glands are a pair of simple tubular glands posteroinferior to the urinary bladder of male mammals...
s
During the 2nd trimester androgen level is associated with Gender identity
Gender identity
A gender identity is the way in which an individual self-identifies with a gender category, for example, as being either a man or a woman, or in some cases being neither, which can be distinct from biological sex. Basic gender identity is usually formed by age three and is extremely difficult to...
This period affects the femininization or masculinization of the fetus and is a better predictor of an adult's femininity or masculinity than an adult's own levels. In other words, an adult's own testosterone level influences behavior less than the mother's during pregnancy.
Early infancy
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 masculinizationVirilization
In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens...
" is occurring since no significant changes have been identified in other parts of the body. Surprisingly, the male brain is masculinized by testosterone being aromatized into estrogen, which crosses the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
and enters the male brain, whereas female fetuses have alpha-fetoprotein
Alpha-fetoprotein
Alpha-fetoprotein is a protein that in humans is encoded by the AFP gene....
which binds up the estrogen so that female brains are not affected.
Pre-peripubertal
Pre- Peripubertal effects are the first observable effects of risingandrogen levels at the end of childhood, occurring in both boys and girls.
- Adult-type body odour
- Increased oiliness of skin and hair, acneAcne vulgarisAcne vulgaris is a common human skin disease, characterized by areas of skin with seborrhea , comedones , papules , pustules , Nodules and possibly scarring...
- PubarchePubarchePubarche refers to the first appearance of pubic hair in a child. Pubarche is one of the physical changes of puberty but should not be equated with it since it may occur independently of complete puberty...
(appearance of pubic hairPubic hairPubic hair is hair in the frontal genital area, the crotch, and sometimes at the top of the inside of the legs; these areas form the pubic region....
) - Axillary hair
- Growth spurt, accelerated bone maturationEpiphysisThe epiphysis is the rounded end of a long bone, at its joint with adjacent bone. Between the epiphysis and diaphysis lies the metaphysis, including the epiphyseal plate...
- HairHairHair is a filamentous biomaterial, that grows from follicles found in the dermis. Found exclusively in mammals, hair is one of the defining characteristics of the mammalian class....
on upper lip and sideburns.
Pubertal
Pubertal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males, these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the blood.- Enlargement of sebaceous glands. This might cause acne.
- Phallic enlargement or clitoromegalyClitoromegalyClitoromegaly is an abnormal enlargement of the clitoris ....
- Increased libidoLibidoLibido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
and frequency of erectionErectionPenile erection is a physiological phenomenon where the penis becomes enlarged and firm. Penile erection is the result of a complex interaction of psychological, neural, vascular and endocrine factors, and is usually, though not exclusively, associated with sexual arousal...
or clitoral engorgement - Pubic hair extends to thighs and up toward umbilicusNavelThe navel is a scar on the abdomen caused when the umbilical cord is removed from a newborn baby...
- Facial hairFacial hairFacial hair is a secondary sex characteristic of human males. Men often start developing facial hair in the later years of puberty or adolescence, approximately between 17–20 years of age, and most do not finish developing a fully adult beard until their early 20s or even later...
(sideburnsSideburnsSideburns or sideboards are patches of facial hair grown on the sides of the face, extending from the hairline to below the ears and worn with an unbearded chin...
, beardBeardA beard is the collection of hair that grows on the chin, cheeks and neck of human beings. Usually, only pubescent or adult males are able to grow beards. However, women with hirsutism may develop a beard...
, moustacheMoustacheA moustache is facial hair grown on the outer surface of the upper lip. It may or may not be accompanied by a type of beard, a facial hair style grown and cropped to cover most of the lower half of the face.-Etymology:...
) - Loss of scalp hair (Androgenetic alopecia)
- Chest hairChest hairThe term chest hair is generally used to describe hair that grows on the chest of human males, in the region between the neck and the abdomen. Chest hair, which is a secondary sex characteristic, develops during and after puberty...
, periareolar hair, perianal hair - Leg hairLeg hairLeg hair is hair that grows on the legs of humans, generally appearing at the onset of adulthood.Male legs are most often hairier than female ones. The amount of hair on an individuals legs can depend on their ethnic background...
- Axillary hair
- Subcutaneous fat in face decreases
- Increased muscle strength and mass
- Deepening of voice
- Growth of the Adam's appleAdam's appleThe laryngeal prominence—commonly known as the Adam's Apple—is a feature of the human neck. This lump, or protrusion, is formed by the angle of the thyroid cartilage surrounding the larynx...
- Growth of spermatogenic tissue in testicles, male fertilityFertilityFertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
- Growth of jawJawThe jaw is any opposable articulated structure at the entrance of the mouth, typically used for grasping and manipulating food. The term jaws is also broadly applied to the whole of the structures constituting the vault of the mouth and serving to open and close it and is part of the body plan of...
, brow, chin, nose, and remodeling of facial bone contours - Shoulders become broader and rib cage expands
- Completion of bone maturation and termination of growth. This occurs indirectly via estradiolEstradiolEstradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
metabolites and hence more gradually in men than women.
Adult
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 decrease in the later decades of adult life.- Testosterone is necessary for normal spermSpermThe term sperm is derived from the Greek word sperma and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell...
development. It activates genes in Sertoli cellSertoli cellA Sertoli cell is a 'nurse' cell of the testes that is part of a seminiferous tubule.It is activated by follicle-stimulating hormone and has FSH-receptor on its membranes.-Functions:...
s, which promote differentiation of spermatogonia. - Regulates acute HPA (Hypothalamic–pituitary–adrenal axis) response under dominance challenge
- Mental and physical energy
- Maintenance of muscle trophism
- Testosterone regulates the population of thromboxane A2Thromboxane A2Thromboxane A2 is a thromboxane. It is produced by activated platelets and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of...
receptors on megakaryocytes and platelets and hence platelet aggregation in humans - Testosterone does not cause or produce deleterious effects on prostate cancerProstate cancerProstate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
. In people who have undergone testosterone deprivation therapy, testosterone increases beyond the castrate level have been shown to increase the rate of spread of an existing prostate cancer. - Recent studies have shown conflicting results concerning the importance of testosterone in maintaining cardiovascular health. Nevertheless, maintaining normal testosterone levels in elderly men has been shown to improve many parameters which are thought to reduce cardiovascular disease risk, such as increased lean body mass, decreased visceral fat mass, decreased total cholesterol, and glycemic control.
- Under dominance challenge, may play a role in the regulation of the fight-or-flight responseFight-or-flight responseThe fight-or-flight response was first described by Walter Bradford Cannon....
- Falling in love decreases men's testosterone levels while increasing women's testosterone levels. It is speculated that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes. It has been found that when the testosterone and endorphins in the ejaculated semen meet the cervical wall after sexual intercourse, females receive a spike in testosterone, endorphin, and oxytocin levels, and males after orgasm during copulation experience an increase in endorphins and a marked increase in oxytocin levels. This adds to the hospitable physiological environment in the female internal reproductive tract for conceiving, and later for nurturing the conceptus in the pre-embryonic stages, and stimulates feelings of love, desire, and paternal care in the male (this is the only time male oxytocin levels rival a female's).
- Recent studies suggest that testosterone levels play a major role in risk-taking during financial decisions.
- The administration of testosterone makes men selfish and more likely to punish others for being selfish towards them.
- Fatherhood also decreases testosterone levels in men, suggesting that the resulting emotional and behavioral changes promote paternal care.
- In animals (grouseGrouseGrouse are a group of birds from the order Galliformes. They are sometimes considered a family Tetraonidae, though the American Ornithologists' Union and many others include grouse as a subfamily Tetraoninae in the family Phasianidae...
and sand lizardSand LizardThe sand lizard is a lacertid lizard distributed across most of Europe and eastwards to Mongolia. It does not occur in the Iberian peninsula or European Turkey. Its distribution is often patchy....
s), higher testosterone levels have been linked to a reduced immune systemImmune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
activity. Testosterone seems to have become part of the honest signaling system between potential mates in the course of evolution.
Brain
As testosterone affects the entire body (often by enlarging; males have bigger hearts, lungs, liver, etc.), the brain is also affected by this "sexual" differentiation; the enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
converts testosterone into estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
that is responsible for masculinization of the brain in male mice. In humans, masculinization of the fetal brain appears, by observation of gender preference in patients with congenital diseases of androgen formation or androgen receptor function, to be associated with functional androgen receptors.
There are some differences between a male and female brain (possibly the result of different testosterone levels), one of them being size: the male human brain is, on average, larger. In a Danish study from 2003, men were found to have a total myelinated fiber length of 176,000 km at the age of 20, whereas in women the total length was 149,000 km.
A study conducted in 1996 found no immediate short term effects on mood or behavior from the administration of supraphysiologic doses of testosterone for 10 weeks on 43 healthy men. Another study found a correlation between testosterone and risk tolerance in career choice among women.
Literature suggests that attention, memory, and spatial ability are key cognitive functions affected by testosterone in humans. Preliminary evidence suggests that low testosterone levels may be a risk factor for cognitive decline and possibly for dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
of the Alzheimer’s type, a key argument in life extension
Life extension
Life extension science, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan...
medicine for the use of testosterone in anti-aging therapies. Much of the literature, however, suggests a curvilinear or even quadratic relationship between spatial performance and circulating testosterone, where both hypo- and hypersecretion (deficient- and excessive-secretion) of circulating androgens have negative effects on cognition and cognitively modulated aggressivity, as detailed above.
Contrary to what has been postulated in outdated studies and by certain sections of the media, aggressive behaviour is not typically seen in hypogonadal men who have their testosterone replaced adequately to the eugonadal/normal range. In fact, aggressive behaviour has been associated with hypogonadism and low testosterone levels and it would seem as though supraphysiological and low levels of testosterone and hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
cause mood disorder
Mood disorder
Mood disorder is the term designating a group of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders classification system where a disturbance in the person's mood is hypothesized to be the main underlying feature...
s and aggressive
Aggressive
“Aggressive” is a New York-based Grammy award-winning music video and commercial directing team of Alex Topaller and Daniel Shapiro.Aggressive has been described by Movie Creation Mag as “having a fascination with the wonderful, in the likes of the surrealist Rafal Olbinski” and “tenacious about...
behaviour, with eugondal/normal testosterone levels being important for mental well-being. Testosterone depletion is a normal consequence of aging in men. One possible consequence of this could be an increased risk for the development of Alzheimer’s disease.
Aggression
The positive correlation between testosterone levels and aggression in humans has been demonstrated in many studies. While testosterone itself is not shown to be the direct cause of aggression in males, the testosterone derivative estradiolEstradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
is known to correlate with aggression in male mice.
Ethnic differences
Different ethnic groups have different incidences of prostate cancerProstate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
. Differences in sex hormones including testosterone have been suggested as an explanation for these differences. A 2009 study found ethnical differences between blacks and whites in the testosterone to sex hormone binding globulin
Sex hormone binding globulin
Sex hormone-binding globulin or sex steroid-binding globulin is a glycoprotein that binds to sex hormones, to be specific, testosterone and estradiol...
ratio in blood from the umbilical cord
Umbilical cord
In placental mammals, the umbilical cord is the connecting cord from the developing embryo or fetus to the placenta...
in infants.
Medical uses
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 hypogonadismHypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
. Appropriate use for this purpose is legitimate hormone replacement therapy (testosterone replacement therapy [TRT]), 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 varying success but higher rates of side effects or problems. Examples include reducing infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
, correcting lack of libido or erectile dysfunction, correcting osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, encouraging penile enlargement
Penis enlargement
Penis enlargement procedures are techniques alleged to make the human penis increase in girth, length, or hardness. Often, in the course of advertising fraudulent products, the distinction between temporary enlargement, i.e...
, encouraging height growth, encouraging bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
stimulation and reversing the effects of anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, and even appetite stimulation. By the late 1940s testosterone was being touted as an anti-aging wonder drug (e.g., see Paul de Kruif
Paul de Kruif
Paul Henry de Kruif was an American microbiologist and author of Dutch descent. Publishing as Paul de Kruif, he is most noted for his 1926 book, Microbe Hunters...
's The Male Hormone). Decline of testosterone production with age has led to interest in androgen replacement therapy
Androgen replacement therapy
Androgen replacement therapy is a hormone treatment often prescribed to counter the effects of male Hypogonadism. It is also prescribed to lessen the effects or delay the onset of normal male aging...
.
To take advantage of its virilizing effects, testosterone is often administered to transsexual men as part of the hormone replacement therapy
Hormone replacement therapy (female-to-male)
Hormone replacement therapy for transgender gender variant and transsexual introduces hormones associate with the gender that the patient identifies with...
, with a "target level" of the normal male testosterone level. Like-wise, transsexual women are sometimes prescribed anti-androgens
Antiandrogen
Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting...
to decrease the level of testosterone in the body and allow for the effects of estrogen to develop.
Testosterone patches are effective at treating low libido in post-menopausal women. Low libido may also occur as a symptom or outcome of hormonal contraceptive use. Women may also use testosterone therapies to treat or prevent loss of bone density, muscle mass and to treat certain kinds of depression and low energy state. Women on testosterone therapies may experience an increase in weight without an increase in body fat due to changes in bone and muscle density. Most undesired effects of testosterone therapy in women may be controlled by hair-reduction strategies, acne prevention, etc. There is a theoretical risk that testosterone therapy may increase the risk of breast or gynaecological cancers, and further research is needed to define any such risks more clearly.
Hormone replacement therapy
Testosterone levels decline gradually with age in human beings. The clinical significance of this decrease is debated (see andropauseAndropause
Andropause or male menopause, sometimes colloquially called "man-opause" is a name that has been given to a menopause-like condition in aging men...
). There is disagreement about when to treat aging men with testosterone replacement therapy. The American Society of Andrology's position is that "testosterone replacement therapy in aging men is indicated when both clinical symptoms and signs suggestive of androgen deficiency
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
and decreased testosterone levels are present." The American Association of Clinical Endocrinologists says "Hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
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 is not total agreement on the threshold of testosterone value below which a man would be considered hypogonadal. (Currently there are no standards as to when to treat women.) Testosterone can be measured as "free" (that is, bioavailable and unbound) or more commonly, "total" (including the percentage which is chemically bound and unavailable). In the United States, male total testosterone levels below 300 ng/dL from a morning serum sample are generally considered low. Identification of inadequate testosterone in an aging male by symptoms alone can be difficult.
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
Hematocrit
The hematocrit or packed cell volume or erythrocyte volume fraction is the percentage of the concentration of red blood cells in blood. It is normally about 45% for men and 40% for women...
which can require venipuncture
Venipuncture
In medicine, venepuncture, venopuncture or venipuncture is the process of obtaining intravenous access for the purpose of intravenous therapy or for blood sampling of venous blood. This procedure is performed by medical laboratory scientists, medical practitioners, some EMTs, paramedics,...
in order to treat, exacerbation of sleep apnea
Sleep apnea
Sleep apnea is a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing, during sleep. Each pause in breathing, called an apnea, can last from a few seconds to minutes, and may occur 5 to 30 times or more an hour. Similarly, each abnormally low...
and acceleration of pre-existing prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
growth in individuals who have undergone androgen deprivation. Another adverse effect may be significant hair loss and/or thinning of the hair. This may be prevented with Propecia (Finasteride), which blocks DHT (a byproduct of testosterone in the body), during treatment. Exogenous testosterone also causes suppression of spermatogenesis
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
and can lead to infertility. It is recommended that physicians screen for prostate cancer with a digital rectal exam and PSA (prostate specific antigen
Prostate specific antigen
Prostate-specific antigen also known as gamma-seminoprotein or kallikrein-3 is a glycoprotein that in humans is encoded by the KLK3 gene. KLK3 is a member of the kallikrein-related peptidase family that are secreted by the epithelial cells of the prostate gland...
) level before starting therapy, and monitor hematocrit and PSA levels closely during therapy.
Benefits
Appropriate testosterone therapy may improve the management of type 2 diabetes,. Low testosterone also brings with it an increased risk for the development of Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. A small trial in 2005 showed mixed results in using testosterone to combat the effects of aging.
Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking.
Adverse effects
Exogenous testosterone supplementation comes with a number of health risks. FluoxymesteroneFluoxymesterone
Fluoxymesterone is an anabolic steroid with strong androgenic properties that has been used in the treatment of male hypogonadism, delayed puberty in males, and in the treatment of breast neoplasms in women. It is approximately 5 times as potent as methyltestosterone...
and methyltestosterone
Methyltestosterone
Methyltestosterone is a 17-alpha-alkylated anabolic steroid used to treat men with a testosterone deficiency. It is also used in women to treat breast cancer, breast pain, swelling due to pregnancy, and with the addition of estrogen it can treat symptoms of menopause...
are synthetic derivatives of testosterone. Methyltestosterone and Fluoxymesterone are no longer prescribed by physicians given their poor safety record, and testosterone replacement in men does have a very good safety record as evidenced by over sixty years of medical use in hypogonadal men.
A 2006 article in Official Journal of the American Urological Association - The Journal of Urology
The Journal of Urology
The Journal of Urology is a peer-reviewed scientific journal of urology published by Elsevier on behalf of the American Urological Association. It was established in 1917.-Editors:*Hugh H. Young *J. A. Campbell Colston...
pointed out that: Prostate cancer may become clinically apparent within months to a few years after the initiation of testosterone treatment. [...] Physicians prescribing testosterone supplementation and patients receiving it should be cognizant of this risk, and serum PSA testing and digital rectal examination should be performed frequently during treatment.
Athletic use
Testosterone can be used by an athlete in order to improve performance, but it is considered to be a form of dopingDoping (sport)
The use of performance-enhancing drugs in sport is commonly referred to by the term "doping", particularly by those organizations that regulate competitions. The use of performance enhancing drugs is mostly done to improve athletic performance. This is why many sports ban the use of performance...
in most sports. There are several application methods for testosterone, including intramuscular injection
Intramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...
s, transdermal gels and patches
Transdermal
Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery, and transdermal implants used for medical or aesthetic purposes....
, and implantable pellets.
Anabolic steroids (including testosterone) have also been taken to enhance muscle development, strength, or endurance. They do so directly by increasing the muscles' protein synthesis. As a result, muscle fibers become larger and repair faster than the average person's.
After a series of scandals and publicity in the 1980s (such as Ben Johnson's improved performance at the 1988 Summer Olympics
1988 Summer Olympics
The 1988 Summer Olympics, officially known as the Games of the XXIV Olympiad, were an all international multi-sport events celebrated from September 17 to October 2, 1988 in Seoul, South Korea. They were the second summer Olympic Games to be held in Asia and the first since the 1964 Summer Olympics...
), prohibition
Prohibition
Prohibition of alcohol, often referred to simply as prohibition, is the practice of prohibiting the manufacture, transportation, import, export, sale, and consumption of alcohol and alcoholic beverages. The term can also apply to the periods in the histories of the countries during which the...
s of anabolic steroid use were renewed or strengthened by many sports organizations. Testosterone and other anabolic steroids were designated a "controlled substance
Controlled substance
A controlled substance is generally a drug or chemical whose manufacture, possession, or use are regulated by a government. This may include illegal drugs and prescription medications ....
" by the United States Congress
United States Congress
The United States Congress is the bicameral legislature of the federal government of the United States, consisting of the Senate and the House of Representatives. The Congress meets in the United States Capitol in Washington, D.C....
in 1990, with the Anabolic Steroid Control Act. The use is seen as being a seriously problematic issue in modern sport, particularly given the lengths to which athletes and professional laboratories go to in trying to conceal such abuse from sports regulators. Steroid abuse once again came into the spotlight recently as a result of the Chris Benoit
Chris Benoit
Christopher Michael "Chris" Benoit was a Canadian professional wrestler whose career and life ended in a murder–suicide...
double murder-suicide in 2007, and the media frenzy surrounding it - however, there has been no evidence indicating steroid use as a contributing factor.
Detection of abuse
A number of methods for detecting testosterone use by athletes have been employed, most based on a urine testUrinalysis
A urinalysis , also known as Routine and Microscopy , is an array of tests performed on urine, and one of the most common methods of medical diagnosis...
. These include the testosterone/epitestosterone
Epitestosterone
Epitestosterone is a natural steroid, an inactive epimer of the hormone testosterone. Structurally, it differs from testosterone only in the configuration at the OH-bearing carbon, C17...
ratio (normally less than 6), the testosterone/luteinizing hormone ratio and the carbon-13
Carbon-13
Carbon-13 is a natural, stable isotope of carbon and one of the environmental isotopes. It makes up about 1.1% of all natural carbon on Earth.- Detection by mass spectrometry :...
/ carbon-12
Carbon-12
Carbon-12 is the more abundant of the two stable isotopes of the element carbon, accounting for 98.89% of carbon; it contains 6 protons, 6 neutrons, and 6 electrons....
ratio (pharmaceutical testosterone contains less carbon-13 than endogenous testosterone). In some testing programs, an individual's own historical results may serve as a reference interval for interpretation of a suspicious finding. Another approach being investigated is the detection of the administered form of testosterone, usually an ester, in hair.
Routes of administration
There are many routes of administration for testosterone. Forms of testosterone for human administration currently available include injectable (such as testosterone cypionate or testosterone enanthate in oil), oral, buccalBuccal
Buccal may refer to:* Mouth, a body cavity** Specifically the cheek* Buccal artery...
, transdermal skin patches, transdermal creams, gels, and implantable pellets. Roll-on methods and nasal sprays are currently under development.
Biosynthesis
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
hormones, testosterone is derived from cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
(see figure to the right). The first step in the biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
involves the oxidative cleavage of the sidechain of cholesterol by CYP11A
Cholesterol side-chain cleavage enzyme
Cytochrome P450, family 11, subfamily A, polypeptide 1 , often referred to as P450scc , is a mitochondrial enzyme associated with the conversion of cholesterol to pregnenolone. The gene name is CYP11A1...
, a mitochondrial
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
cytochrome P450 oxidase with the loss of six carbon atoms to give pregnenolone
Pregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...
. In the next step, two additional carbon atoms are removed by the CYP17A enzyme in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
to yield a variety of C19 steroids. In addition, the 3-hydroxyl group is oxidized by 3-β-HSD
3-beta-HSD
3-β-HSD is an enzyme that catalyses the synthesis of progesterone from pregnenolone, 17-hydroxyprogesterone from 17-hydroxypregnenolone, and androstenedione from dehydroepiandrosterone in the adrenal gland...
to produce androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
. In the final and rate limiting step, the C-17 keto group androstenedione is reduced by 17-β hydroxysteroid dehydrogenase
17Beta Hydroxysteroid dehydrogenase
The 17β-hydroxysteroid dehydrogenases are a group of alcohol oxidoreductases which catalyse the dehydrogenation of 17-hydroxysteroids in steroidogenesis.Note that the major reactions catalysed by 17β-HSD The 17β-hydroxysteroid dehydrogenases (17β-HSD enzymes) are a group of alcohol oxidoreductases...
to yield testosterone.
The largest amounts of testosterone (>95%) are produced by the testes in men. It is also synthesized in far smaller quantities in women by the thecal cells of the ovaries
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
, by the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, as well as by the zona reticularis
Zona reticularis
The zona reticularis is the innermost layer of the adrenal cortex, lying deep to the zona fasciculata and superficial to the adrenal medulla. The cells are arranged cords that project in different directions giving a net-like appearance The zona reticularis is the innermost layer of the adrenal...
of the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
in both sexes. In the testes, testosterone is produced by the Leydig cell
Leydig cell
Leydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle. They produce testosterone in the presence of luteinizing hormone...
s. The male generative glands also contain Sertoli cell
Sertoli cell
A Sertoli cell is a 'nurse' cell of the testes that is part of a seminiferous tubule.It is activated by follicle-stimulating hormone and has FSH-receptor on its membranes.-Functions:...
s which require testosterone for spermatogenesis
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
. 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
Sex hormone binding globulin
Sex hormone-binding globulin or sex steroid-binding globulin is a glycoprotein that binds to sex hormones, to be specific, testosterone and estradiol...
(SHBG).
Regulation
In males, testosterone is primarily synthesized in Leydig cells. The number of Leydig cells in turn is regulated by luteinizing hormoneLuteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
(LH) and follicle stimulating hormone (FSH). In addition, the amount of testosterone produced by existing Leydig cells is under the control of LH which regulates the expression of 17-β hydroxysteroid dehydrogenase.
The amount of testosterone synthesized is regulated by the hypothalamic-pituitary-testicular axis
Hypothalamic-pituitary-gonadal axis
The hypothalamic–pituitary–gonadal axis refers to the effects of the hypothalamus, pituitary gland, and gonads as if these individual endocrine glands were a single entity as a whole...
(see figure to the right). When testosterone levels are low, gonadotropin-releasing hormone (GnRH
Gonadotropin-releasing hormone
Gonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...
) is released by the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
which in turn stimulates the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
to release FSH and LH. These later two hormones stimulate the testis to synthesize testosterone. Finally increasing levels of testosterone through a negative feedback
Feedback
Feedback describes the situation when output from an event or phenomenon in the past will influence an occurrence or occurrences of the same Feedback describes the situation when output from (or information about the result of) an event or phenomenon in the past will influence an occurrence or...
loop act on the hypothalamus and pituitary to inhibit the release of GnRH and FSH/LH respectively.
Environmental factors affecting testosterone levels include:
- Implicit power motivation predicts an increased testosterone release in men.
- Aging reduces testosterone release.
- HypogonadismHypogonadismHypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
- Sleep (REM dream) increases nocturnal testosterone levels.
- Resistance trainingResistance trainingResistance training has two different meanings. A broader meaning that refers to any training that uses a resistance to the force of muscular contraction , and elastic or hydraulic resistance, which refers to a specific type of strength training that uses elastic or hydraulic tension to provide...
increases testosterone levels, however, in older men, that increase can be avoided by protein ingestion. - ZincZincZinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
deficiency lowers testosterone levels but over supplementation has no effect on serum testosterone. - Licorice. The active ingredient in licorice root, glycyrrhizinic acid has been linked to small, clinically non-significant decreases in testosterone levels. In contrast, a more recent study found that licorice administration produced a substantial testosterone decrease in a small, female-only sample.
- Natural or man-made antiandrogens including spearmintSpearmintMentha spicata syn. M. cordifolia is a species of mint native to much of Europe and southwest Asia, though its exact natural range is uncertain due to extensive early cultivation. It grows in wet soils...
tea reduce testosterone levels.
Metabolism
Approximately 7% of testosterone is reduced to 5α-dihydrotestosteroneDihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
(DHT) by the cytochrome P450 enzyme 5α-reductase
5-alpha reductase
5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism, and prostate cancer....
, an enzyme highly expressed in male accessory sex organs and hair follicles. Approximately 0.3% of testosterone is converted into estradiol by aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
(CYP19A1) an enzyme expressed in the brain, liver, and adipose tissues.
DHT is a more potent form of testosterone while estradiol has completely different activities (feminization) compared to testosterone (masculinization). Finally testosterone and DHT may be deactivated or cleared by enzymes that hydroxylate at the 6, 7, 15 or 16 positions.
Mechanism of action
The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptorAndrogen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
(directly or as DHT), and by conversion to estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
and activation of certain estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
s.
Free testosterone (T) is transported into the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
of target tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
, where it can bind to the androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
, or can be reduced to 5α-dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
(DHT) by the cytoplasmic enzyme 5-alpha reductase
5-alpha reductase
5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism, and prostate cancer....
. DHT binds to the same androgen receptor even more strongly than testosterone, so that its androgenic potency is about 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
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and bind directly to specific nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
sequences of the chromosomal
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
DNA. The areas of binding are called hormone response element
Hormone response element
A hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
s (HREs), and influence transcriptional activity of certain gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, 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
Sexual differentiation
Sexual differentiation is the process of development of the differences between males and females from an undifferentiated zygote...
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
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
. In the bones, estradiol accelerates maturation of cartilage into bone, leading to closure of the epiphyses
Epiphysis
The epiphysis is the rounded end of a long bone, at its joint with adjacent bone. Between the epiphysis and diaphysis lies the metaphysis, including the epiphyseal plate...
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
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
secretion). In many mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s, prenatal or perinatal "masculinization" of the sexually dimorphic
Sexual dimorphism
Sexual dimorphism is a phenotypic difference between males and females of the same species. Examples of such differences include differences in morphology, ornamentation, and behavior.-Examples:-Ornamentation / coloration:...
areas of the brain by estradiol derived from testosterone programs later male sexual behavior.
The human hormone testosterone is produced in greater amounts by males, and less by females. The human hormone estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
is produced in greater amounts by females, and less by males. Testosterone causes the appearance of masculine traits (i.e., deepening voice, pubic and facial hairs, muscular build, etc.) Like men, women rely on testosterone to maintain libido, bone density and muscle mass throughout their lives. In men, inappropriately high levels of estrogens lower testosterone, decrease muscle mass, stunt growth in teenagers, introduce gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
, increase feminine characteristics, and decrease susceptibility to prostate cancer, reduces libido and causes erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
and can cause excessive sweating and hot flushes . However, an appropriate amount of estrogens is required in the male in order to ensure well-being, bone density, libido, erectile function, etc.
Synthetic analogs
A number of synthetic analogs of testosterone have been developed with improved bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
and metabolic half life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
relative to testosterone. Many of these analogs have an alkyl group introduced at the C-17 position in order to prevent conjugation and hence improve oral bioavailability. These are the so-called “17-aa” (17-alkyl androgen) family of androgens such as fluoxymesterone
Fluoxymesterone
Fluoxymesterone is an anabolic steroid with strong androgenic properties that has been used in the treatment of male hypogonadism, delayed puberty in males, and in the treatment of breast neoplasms in women. It is approximately 5 times as potent as methyltestosterone...
and methyltestosterone
Methyltestosterone
Methyltestosterone is a 17-alpha-alkylated anabolic steroid used to treat men with a testosterone deficiency. It is also used in women to treat breast cancer, breast pain, swelling due to pregnancy, and with the addition of estrogen it can treat symptoms of menopause...
.
Related drugs
Some drugs indirectly target testosterone as a way of treating certain conditions. For example, 5-alpha-reductase inhibitor5-alpha-reductase inhibitor
5α-Reductase inhibitors are a group of drugs with antiandrogenic activity, used in the treatment of benign prostatic hyperplasia and androgenic alopecia...
s such as finasteride
Finasteride
Finasteride is a synthetic antiandrogen that inhibits type II 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone...
inhibits the conversion of testosterone into dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
(DHT), a metabolite which is more potent than testosterone. These 5-alpha-reductase inhibitors have been used to treat various conditions associated with androgens, such as androgenetic alopecia
Androgenetic alopecia
Androgenic alopecia is the most common cause of hair loss and thinning in humans. Variants appear in both men and women. Androgenic alopecia also occurs in chimpanzees, and orangutans. In humans, this condition is also commonly known as male pattern baldness...
(male-pattern baldness), hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
, benign prostatic hyperplasia
Benign prostatic hyperplasia
Benign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate....
(BPH), and prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
. Alternatively GnRH antagonists
Gonadotropin-releasing hormone antagonist
Gonadotrophin-releasing hormone antagonists are a class of compounds that are similar in structure to natural GnRH but that have an antagonistic effect. GnRH antagonists are peptide molecules that are made up multiple, often synthetically produced amino acids...
bind to GnRH receptors
Gonadotropin-releasing hormone receptor
The gonadotropin-releasing hormone receptor , also known as the luteinizing hormone releasing hormone receptor , is a member of the seven-transmembrane, G-protein coupled receptor family...
in the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
, blocking the release of luteinising hormone (LH) and follicle-stimulating hormone
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH) from the pituitary. In men, the reduction in LH subsequently leads to rapid suppression of testosterone release from the testes. GnRH antagonists have been used for the treatment of prostate cancer.
Insufficiency
Testosterone insufficiency (also termed hypotestosteronism or hypotestosteronemia) is an abnormally low testosterone production. It may occur because of testicular dysfunction (primary hypogonadism) or hypothalamic-pituitary dysfunction (secondary hypogonadism) and may be congenital or acquired. An acquired form of hypotestosteronism is a decline in testosterone levels that occurs by aging, sometimes being called "andropauseAndropause
Andropause or male menopause, sometimes colloquially called "man-opause" is a name that has been given to a menopause-like condition in aging men...
" in men, as a comparison to the decline in estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
that comes with menopause
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
in women.
History
A testicular action was linked to circulating blood fractions – now understood to be a family of androgenic hormones – in the early work on castration and testicular transplantation in fowl by Arnold Adolph BertholdArnold Adolph Berthold
Arnold Adolph Berthold or Arnold Adolf Berthold was a German physiologist and zoologist. He studied medicine in Göttingen in 1819 and wrote his thesis under the direction of Johann Friedrich Blumenbach . Berthold became a private lecturer in 1825 and began to teach physiology at the University of...
(1803–1861). Research on the action of testosterone received a brief boost in 1889, when the Harvard professor Charles-Édouard Brown-Séquard
Charles-Édouard Brown-Séquard
Charles-Édouard Brown-Séquard FRS , also known as Charles Edward, was a Mauritian physiologist and neurologist who, in 1850, became the first to describe what is now called Brown-Séquard syndrome.-Early life:...
(1817–1894), then in Paris, self-injected subcutaneously a “rejuvenating elixir” consisting of an extract of dog and guinea pig testicle. He reported in The Lancet that his vigor and feeling of well-being were markedly restored but, predictably, the effects were transient (and likely based on a placebo effect), and Brown-Séquard’s hopes for the compound were dashed. Suffering the ridicule of his colleagues, his work on the mechanisms and effects of androgens in human beings was abandoned by Brown-Séquard and succeeding generations of biochemists for nearly 40 years.
The trail remained cold until the University of Chicago’s Professor of Physiologic Chemistry, Fred C. Koch, established easy access to a large source of bovine testicles—the Chicago stockyards—and to students willing to endure the ceaseless toil of extracting their isolates. In 1927, Koch and his student, Lemuel McGee, derived 20 mg of a substance from a supply of 40 pounds of bovine testicles that, when administered to castrated roosters, pigs and rats, remasculinized them. The group of Ernst Laqueur at the University of Amsterdam purified testosterone from bovine testicles in a similar manner in 1934, but isolation of the hormone from animal tissues in amounts permitting serious study in humans was not feasible until three European pharmaceutical giants—Schering
Schering
Schering AG was a research-centered German pharmaceutical company. It was founded in 1851 by Ernst Christian Friedrich Schering and merged with Bayer's pharma sector in December 2006. The company's headquarters was in Berlin-Wedding, Germany...
(Berlin, Germany), Organon
Organon International
Organon is a human pharmaceutical company headquartered in Oss, Netherlands. In November 2007 the company became a part of Schering-Plough Corporation, acquired Organon, active pharmaceutical ingredient producer Diosynth , and its veterinary pharmaceutical sister company Intervet from Akzo Nobel. ...
(Oss, Netherlands) and Ciba (Basel, Switzerland)—began full-scale steroid research and development programs in the 1930s.
The Organon group in the Netherlands were the first to isolate the hormone, identified in a May 1935 paper "On Crystalline Male Hormone from Testicles (Testosterone)". They named the hormone testosterone, from the stems of testicle and sterol
Sterol
Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol...
, and the suffix
Suffix
In linguistics, a suffix is an affix which is placed after the stem of a word. Common examples are case endings, which indicate the grammatical case of nouns or adjectives, and verb endings, which form the conjugation of verbs...
of ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
. The structure was worked out by Schering’s Adolf Butenandt
Adolf Butenandt
Adolf Friedrich Johann Butenandt was a German biochemist and member of the Nazi party. He was awarded the Nobel Prize in Chemistry in 1939 for his "work on sex hormones." He initially rejected the award in accordance with government policy, but accepted it in 1949 after World War...
.
The chemical synthesis
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
of testosterone from cholesterol was achieved in August that year by Butenandt and Hanisch. Only a week later, the Ciba group in Zurich, Leopold Ruzicka (1887–1976) and A. Wettstein, published their synthesis of testosterone. These independent partial syntheses of testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939 Nobel Prize in Chemistry
Nobel Prize in Chemistry
The Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...
. Testosterone was identified as 17β-hydroxyandrost-4-en-3-one (C19H28O2), a solid polycyclic alcohol with a hydroxyl group at the 17th carbon atom. This also made it obvious that additional modifications on the synthesized testosterone could be made, i.e., esterification and alkylation.
The partial synthesis in the 1930s of abundant, potent testosterone esters permitted the characterization of the hormone’s effects, so that Kochakian and Murlin (1936) were able to show that testosterone raised nitrogen retention (a mechanism central to anabolism) in the dog, after which Allan Kenyon’s group was able to demonstrate both anabolic and androgenic effects of testosterone propionate in eunuchoidal men, boys, and women. The period of the early 1930s to the 1950s has been called "The Golden Age of Steroid Chemistry", and work during this period progressed quickly. Research in this golden age proved that this newly synthesized compound—testosterone—or rather family of compounds (for many derivatives were developed from 1940 to 1960), was a potent multiplier of muscle, strength, and well-being.