Testosterone

Testosterone
Systematic name
IUPAC name 17β-hydroxy-4-androsten-3-one
Identifiers
CAS number	58-22-0
ATC code	G03BA03
PubChem	6013
Chemical data
Formula	C19H28O2
Mol. weight	288.43
Physical data
Melt. point	155-156°C (-94°F)
Spec. rot	+110,2°
SEC Combust	−11080 kJ/mol
Pharmacokinetic data
Bioavailability	?
Metabolism	Liver, Testis and Prostate
Half life	1-12 days
Excretion	Urine
Therapeutic considerations
Pregnancy cat.	X (USA), Teratogenic effects
Legal status	Schedule III (USA) Schedule IV (Canada)
Routes	Intramuscular injection, transdermal (cream, gel, or patch), oral, sub-'Q' pellet

Testosterone is a steroid hormone with the chemical formula C₁₉H₂₈O₂; along with other members of the androgen group, testosterone is involved in coordinating the development and maintenance of male secondary sex characteristics.

This chemical messenger is primarily synthesized in the testes of males, although small amounts are also secreted by the female ovaries and the adrenal glands of both sexes.

Testosterone's effects can be classified as anabolic (related to protein synthesis and growth) and virilizing (the biological development of male sex characteristics); however, the two categories are closely related:

• Anabolic effects include growth of muscle mass, increased bone density, and stimulation of linear growth and bone maturation.
• Virilizing effects (also known as androgenic effects) include maturation of the sex organs, particularly the penis and the formation of the scrotum in the male fetus. During puberty, testosterone also coordinates development of masculine characteristics such as a deepening of the voice and growth of facial hair.

On average, the adult male human produces about twenty to thirty times the amount of testosterone synthesized by an adult female (Larsen, et al., 2002).Nonetheless, like men, women rely on testosterone (albeit in significantly smaller quantities) to maintain libido, bone density and muscle mass throughout their lives.

anabolic steroids: Talk about positive (and possibly negative effects) in our culture and animal societies

Helpful and problematic use of synthetic testosterone.

Structure and classification

Like other steroid hormones, testosterone is derived from cholesterol. Androgens (such as testosterone) are responsible for the development of male secondary sex characteristics (other androgens include x y z).

Steroids characterized by a carbon skeleton w/ four fused rings; distinguished by the functional groups attached to the rings.

The presence of the hydroxyl group proved important, for two reasons.

First, the hydroxyl group made it obvious that testosterone could be esterified, or altered by the substitution of an acid group for the hydroxyl group at the C17 position. Esterification lowers the water solubility of the molecule and increases its lipid solubility, permitting a sterile oil-based injectible to form a “depot” in the muscle, from which it is gradually released. Esterification temporarily deactivates the steroid molecule, because the presence of the large acid chain prevents the steroid from binding to androgen receptor (AR) molecules within muscle cells that promote protein synthesis. But, as the esterified steroid is gradually leached from the oily depot into the blood, esterases (acid-cleaving molecules) replace the acid chain with a hydroxyl group as in the virgin molecule, permitting the steroid to bind to AR. The overall effect of esterification is to extend the steroid’s half-life, ease its administration, and alter its anabolic/androgenic ratio (A/AR), or the degree to which it affects striated muscle vs. sexual organ tissues such as the testes or prostate.

The second important implication of the hydroxyl side chain at the C-17 position was that it permitted, not just esterification, but also alkylation of the steroid molecule (substitution of an ethyl or methyl group for the hydroxyl group). Alkylation was to permit the development of oral steroids, the so-called “17-aa” or alkylated family of androgens such as methyltestosterone, which could be taken up by the digestive track, and so be easily administered in pill form.

Production

The largest amounts of testosterone are produced by the testes in men, but it is also synthesized in smaller quantities in women by the thecal cells of the ovaries, by the placenta, as well as by the zona reticularis of the adrenal cortex in both sexes.

In the testes, testosterone is produced by the Leydig cells. The male generative glands also contain Sertoli cells which require testosterone for spermatogenesis.

How testosterone works as a signaling molecule

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).

The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors.

In the first method, 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 an enzyme in the cytoplasm. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects.

The bones and the brain are two important tissues in humans where the primary effect of testosterone is by way of aromatization to estradiol, testosterone’s second method of action. 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 mammals, prenatal or perinatal "masculinization" of the sexually dimorphic areas of the brain by estradiol derived from testosterone programs later male sexual behavior.

Regulation

leutenizing hormone, eg

Testosterone's role in growth and development

Testosterone effects can be classified by the age of usual occurrence. Postnatal effects in both males and females are mostly dependent on the levels and duration of circulating free testosterone.

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. Intrauterine exposure to these hormones fosters aggression in females: female mice that are snuggled between their brothers during fetal life are exposed to higher levels of androgens than females nestled between sisters and are more aggressive adults; intrauterine exposure also leads to profound genital abnormalities. In humans, for example, excessive exposure to androgens in the womb gives a girl a greatly enlarged clitoris and a vagina that is partially fused shut.

Most of the prenatal androgen effects occur between 7 and 12 weeks of gestation.

• Genital virilization (midline fusion, phallic urethra, scrotal thinning and rugation, phallic enlargement); although the role of testosterone is far smaller than that of Dihydrotestosterone.
• Development of prostate and seminal vesicles

Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4-6 months of age. The function of this rise in humans is unknown. It has been speculated that "brain masculinization" is occurring since no significant changes have been identified in other parts of the body. (????)

Early postnatal effects are the first visible effects of rising androgen levels in childhood, and occur in both boys and girls in puberty.

• Adult-type body odour
• Increased oiliness of skin and hair, acne
• Pubarche (appearance of pubic hair)
• Axillary hair
• Growth spurt, accelerated bone maturation
• Fine upper lip and sideburn hair

Advanced postnatal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the blood.

• Phallic enlargement (including clitoromegaly)
• Increased libido and frequency of erection or clitoral engorgement
• Pubic hair extends to thighs and up toward umbilicus
• Facial hair (sideburns, beard, moustache)
• Chest hair, periareolar hair, perianal hair
• Subcutaneous fat in face decreases
• Increased muscle strength and mass
• Deepening of voice
• Growth of the adam's apple
• Growth of spermatogenic tissue in testes, male fertility
• Growth of jaw, brow, chin, nose, and remodeling of facial bone contours
• Shoulders widen and rib cage expands
• Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women.

Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels decline in the later decades of adult life.

• Maintenance of muscle mass and strength
• Maintenance of bone density and strength
• Libido and clitoral engorgement/penile erection frequency.
• Mental and physical energy
• Excessive testosterone in males can lead to an increased risk of prostate cancer although some recent studies suggest that the role of testosterone has less of a potentiating effect on prostate cancer, but that oestrogen has more of a role.

Possible behavioral affects

many vertebrate brain structures involved in the control of aggression are supplied w/ receptors for steroid hormones produced in the gonads; behavioral affects are more difficult to understand/to attribute to a given cause, but the level of circulating testosterone has been correlated to aggression in a variety of vertebrate species: for elephant bulls in musth (young ones, only a few days at a time, older ones for as long as four months), the amt of testosterone in the blood soars to levels fifty times higher than usual; musth as mix of desperate lust and rage, more likely to engage in fights w/ other males in musth (however, complicated: other hormones might be involved in control of aggression, such as vasotocin and vasopressin; in addition, link might work in the other direction; also keep in mind that a given hormone can have v. different effects on behavior depending on the region of the central nervous system on which it acts

moreover, seems to be more closely associated w/ aggression related to reproduction, such as the territorial and mate-guarding behavior of male red-winged blackbirds (agelaius phoeniceus), in whom testosterone levels peak during the two-week period when males are defending breeding territories and guarding their mates from rivals (barnard 152)

Animal models of the effects of supraphysiological doses of testosterone suggest that it alters aggression, sexual behaviors, anxiety, reward, and learning and the neurotransmitter systems and brain areas that underlie these behaviors (Clark and Henderson, 2003). A number of studies and reviews (e.g., Bahrke et al, 1990) have linked testosterone use in humans to significant psychiatric disturbances including depression, psychosis, and aggression. Experimental evidence suggests that supraphysiologic doses of testosterone may lead to mania in a small number of men (Pope et al, 2000). Depressive symptoms have been noted particularly during AAS withdrawal (Brower, 2002). At least one study suggests that testosterone users are more likely to die of suicide or homicide than amphetamine or heroine users (Petersson et al, in press) and to die younger than non-using weightlifting controls (Parssinen et al, 2000). There is gathering support from animal research for a model in which testosterone and others steroids use cause increased hypothalamic activation, euphoria, and energy, which most users find pleasant, but which might also cause increased distractibility and for some morphs into mania or into depression during drug abstinence. This activation may lead to threat-wariness and irritability, resulting in greater aggression.

Therapeutic uses

Testosterone was first isolated from a bull in 1935. There have been many pharmaceutical forms over the years. Forms of testosterone for human administration currently available in North America include injectable (such as testosterone cypionate or testosterone enanthate in oil), oral Andriol, buccal Striant, transdermal skin patches, and transdermal creams or gels Androgel and Testim. In the pipeline are "roll on" methods and nasal sprays.

The original and primary use of testosterone is for the treatment of males who have too little or no natural endogenous (exp) testosterone production—males with hypogonadism. Appropriate use for this purpose is legitimate hormone replacement therapy, which maintains blood testosterone levels in the normal range.

However, over the years, as with every hormone, testosterone or other anabolic steroids has also been given for many other conditions and purposes besides replacement, with variable success but higher rates of side effects or problems. Examples include the use of testosterone to treat infertility, lack of libido or erectile dysfunction, osteoporosis, penile enlargement, height growth, bone marrow stimulation and reversal of anemia, and even appetite stimulation. By the late 1940s testosterone was being touted as an anti-aging wonder drug (e.g., see Paul de Kruif's The Male Hormone). Decline of testosterone production with age has led to a demand for Androgen Replacement Therapy.

To take advantage of its virilizing effects, testosterone is often administered to female-to-male transsexual men as part of the hormone replacement therapy, with a "target level" of the normal male testosterone level. Like-wise, male-to-female transsexual women are sometimes prescribed drugs [anti-androgens] to decrease the level of testosterone in the body and allow for the effects of estrogen to develop.

Women use testosterones to treat low libido, often 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 non-transgendered women (the majority) may be controlled by hair-reduction strategies, acne prevention, etc.

Some drugs specifically target testosterone as a way of treating certain conditions. For example, finasteride inhibits the conversion of testosterone into dihydrotestosterone (DHT), a metabolite that is more potent than testosterone. By lowering the levels of dihydrotestosterone, finasteride may be used for various conditions associated with androgens, such as benign prostatic hyperplasia (BPH) and androgenetic alopecia (male-pattern baldness).

Athletic use

(more on test as a synthetic and on anabolic steroids in athletic/bodybuilding context; photo of ben Johnson?) Testosterone may be administered to an athlete in order to improve performance, and is considered to be a form of doping in most sports. There are several application methods for testosterone, including intramuscular injections, transdermal gels and patches, and implantable pellets.

Anabolic steroids (of which testosterone is one) 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 more quickly 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), prohibitions of anabolic steroid use were renewed or strengthened by many sports organizations. Testosterone and other anabolic steroids were designated a "controlled substance" by the United States Congress in 1990, under the Anabolic Steroid Control Act. [1]

Changes during aging

Testosterone levels decline gradually with age in human beings. The clinical significance of this decrease is debated (see andropause). There is disagreement about if and when to treat aging men with testosterone replacement therapy. The American Society of Andrology's position is that testosterone therapy "is indicated when both clinical symptoms and signs suggestive of androgen deficiency and decreased testosterone levels are present". The American Association of Clinical Endocrinologists says "Hypogonadism is defined as a free testosterone level that is below the lower limit of normal for young adult control subjects. Previously, age-related decreases in free testosterone were once accepted as normal. Currently, they are not considered normal....Patients with low-normal to subnormal range testosterone levels warrant a clinical trial of testosterone." [2]

There isn't 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 200 to 300 ng/dl from a morning sample are generally considered low. However these numbers are typically not age-adjusted, but based on an average of a test group which includes elderly males with low testosterone levels. Therefore a value of 300 ng/dl might be normal for a 65 year old male, but not normal for a 30 year old. Identification of inadequate testosterone in an aging male by symptoms alone can be difficult. The signs and symptoms are non-specific, and might be confused with normal aging characteristics, such as loss of muscle mass and bone density, decreased physical endurance, decreased memory ability and loss of libido.

Replacement therapy can take the form of injectable depots, transdermal patches and gels, subcutaneous pellets and oral therapy. Adverse effects of testosterone supplementation include minor side effects such as acne and oily skin, and more significant complications such as increased hematocrit, exacerbation of sleep apnea and acceleration of pre-existing prostate cancer growth. Exogenous testosterone also causes suppression of spermatogenesis and can lead to infertility. It is recommended that physicians screen for prostate cancer with a digital rectal exam and PSA (prostate specific antigen) level prior to initiating therapy, and monitor hematocrit and PSA levels closely during therapy.

Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking. Many caution against embracing testosterone replacement therapy because of lessons from the female hormone replacement therapy trials, where initially promising results were later refuted by larger studies. Still, testosterone replacement therapies in women to treat/prevent osteoporosis have yet to show the risks now shown with estrogen replacement therapies.

Additional images

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  Steroidogenesis

References

ISBN links support NWE through referral fees

• Barnard, C. 2004. Animal Behaviour: Mechanism, Development, Function and Evolution. Harlow, England: Pearson/Prentice Hall. ISBN: 0-130-89936-4
• Judson, O. 2002. Dr. Tatiana’s Sex Advice to All Creation: The Definitive Guide to the Evolutionary Biology of Sex New York, NY: Metropolitan Books. ISBN 0-805-06331-5
• Larsen, P.R., Kronenberg, H.M., Melmed, S., Polonsky, K.S., Foster, D.W., and J.D. Wilson 2002. Williams Textbook of Endocrinology, 3rd ed. New York, NY: Saunders.

External links

• NIST entry for Testosterone
• NIST results of search for Testosterone (Shows androstenone.)

Template:ChemicalSources

Hormones and endocrine glands

Hypothalamus: GnRH - TRH - CRH - GHRH - somatostatin - dopamine | Posterior pituitary: vasopressin - oxytocin | Anterior pituitary: GH - ACTH - TSH - LH - FSH - prolactin - MSH - endorphins - lipotropin Thyroid: T3 and T4 - calcitonin | Parathyroid: PTH | Adrenal medulla: epinephrine - norepinephrine | Adrenal cortex: aldosterone - cortisol - DHEA | Pancreas: glucagon- insulin - somatostatin | Ovary: estradiol - progesterone - inhibin - activin | Testis: testosterone - AMH - inhibin | Pineal gland: melatonin | Kidney: renin - EPO - calcitriol - prostaglandin | Heart atrium: ANP Stomach: gastrin | Duodenum: CCK - GIP - secretin - motilin - VIP | Ileum: enteroglucagon | Liver: IGF-1 Placenta: hCG - HPL - estrogen - progesterone Adipose tissue: leptin, adiponectin Target-derived NGF, BDNF, NT-3

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