Tuesday, November 13, 2012

Natural Testosterone by Testoril


Testosterone     


Testosterone
Systematic (IUPAC) name
(8R,9S,10R,13S,14S,17S)- 17-hydroxy-10,13-dimethyl- 1,2,6,7,8,9,11,12,14,15,16,17- dodecahydrocyclopenta[a]phenanthren-3-one
Clinical data
Trade namesAndroderm, Delatestryl
AHFS/Drugs.commonograph
Pregnancy cat.X (USA), Teratogeniceffects
Legal statusSchedule III (USA)
Schedule IV (Canada)
RoutesIntramuscular injection, transdermal (cream, gel, or patch), sub-'Q' pellet
Pharmacokinetic data
Bioavailabilitylow (due to extensive first pass metabolism)
MetabolismLiver, Testis and Prostate
Half-life2–4 h
ExcretionUrine (90%), feces (6%)
Identifiers
CAS number58-22-0 Yes
57-85-2 (propionate ester)
ATC codeG03BA03
PubChemCID 6013
IUPHAR ligand2858
DrugBankDB00624
ChemSpider5791 Yes
UNII3XMK78S47O Yes
KEGGD00075 Yes
ChEBICHEBI:17347 
ChEMBLCHEMBL386630 Yes
Chemical data
FormulaC19H28O2 
Mol. mass288.42
Physical data
Melt. point155 °C (311 °F)
Spec. rot+110.2°
SEC Combust−11080 kJ/mol
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Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles,[1] birds,[2] and other vertebrates. In mammals, testosterone is primarily secreted in the testicles of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. 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.[3] In addition, testosterone is essential for health and well-being[4] as well as the prevention of osteoporosis.[5]
On average, in adult human males, the plasma concentration of testosterone is about 7-8 times as great as the concentration in adult human females' plasma,[6] but as the metabolic consumption of testosterone in males is greater, the daily production is about 20 times greater in men.[7][8] Females also are more sensitive to the hormone.[9] Testosterone is observed in most vertebrates. Fish make a slightly different form called 11-ketotestosterone.[10] Its counterpart in insects is ecdysone.[11] These ubiquitous steroids suggest that sex hormones have an ancient evolutionary history.[12]

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In general, androgens promote protein synthesis and growth of those tissues withandrogen receptors. Testosterone effects can be classified as virilizing and anabolic, though the distinction is somewhat artificial, as many of the effects can be considered both.Physiological effects

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.

[edit]Prenatal

The prenatal androgen effects occur during two different stages. Between 4 and 6 weeks of the gestation.
During the 2nd trimester androgen level is associated with Gender identity[13] This period affects the femininization or masculinization of the fetus and can be a better predictor of feminine or mascular behaviours such as sex typed behaviour than an adult's own levels. A mother's own testosterone level influences behavior more than the daughters's testosterone level during pregnancy.[14]

[edit]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.[15][16]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.[17] 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.[18]

[edit]Pre-peripubertal

Pre- Peripubertal effects are the first observable effects of rising androgen levels at the end of childhood, occurring in both boys and girls.

[edit]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.

[edit]

[edit]Biological uses

[edit]Cancer prevention and health risks

  • Testosterone does not cause or produce deleterious effects on prostate cancer. 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.[24][25][26]
  • Recent studies have shown conflicting results concerning the importance of testosterone in maintaining cardiovascular health.[27][28]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.[29]
  • Under dominance challenge, may play a role in the regulation of the fight-or-flight response[30]
  • Men whose testosterone levels are slightly above average are less likely to have high blood pressure, less likely to experience a heart attack, less likely to be obese, and less likely to rate their own health as fair or poor. However, high testosterone men are more likely to report one or more injuries, more likely to consume five or more alcoholic drinks in a day, more likely to have had a sexually transmitted infection, and more likely to smoke.[31]

[edit]Romantic relationships and fatherhood

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.[32] However, it is suggested that after the “honeymoon phase” ends, approximately 1–3 years into the relationship, this change in testosterone levels is no longer apparent.[32]Fatherhood also decreases testosterone levels in men, suggesting that the resulting emotional and behavioral changes promote paternal care.[33] Both heterosexual and non-heterosexual men producing less testosterone are more likely to be in a relationship[34]and/or married,[35] and that men producing more testosterone are more likely to divorce.[35] However, causality cannot be determined in this relationship. Marriage or commitment could actually cause a decrease in T levels.[36] Single men, who do not have relationship experience, have lower testosterone levels than single men with experience. It is suggested that these single men with prior experience are in a more competitive state than their non-experienced counterparts.[37] Furthermore, it has been found that married men who engage in bond-maintenance activities such as spending the day with their wife/and or child have no different testosterone levels compared to times when they do not engage in such activities. Collectively, these results suggest that it is the presence of competitive activities rather than bond-maintenance activities that are more relevant to changes in T levels.[38]
Men producing more testosterone are also more likely to engage in extramarital sex.[35]
Testosterone levels do not rely on physical presence of a partner for men engaging in relationships (same-city vs. long-distance), men have similar testosterone levels across the board.[34]
Physical presence may be required for women who are in relationships for the testosterone-partner interaction, where same-city partnered women have lower testosterone levels than long-distance partnered women.[39]

[edit]Testosterone and sexual arousal

It has been found that when testosterone and endorphins in 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).[32]
Testosterone levels follow a nyctohemeral rhythm which peaks early each day, regardless of sexual activity[40]
There are positive correlations between positive orgasm experience in women and testosterone levels where relaxation was a key perception of the experience. There is no correlation between testosterone and men’s perceptions of their orgasm experience, and also no correlation between higher testosterone levels and greater sexual assertiveness in either sex.[41]
An increase in T levels has also been found to occur in both men and women who have orgasms that are masturbation-induced.[42][43]
[edit]Mammalian studies
Studies conducted on rats have indicated that their degree of sexual arousal is sensitive to reductions in testosterone. When testosterone-deprived rats were given medium levels of testosterone, their sexual behaviors (copulation, partner preference, etc.) resumed, but not when given low amounts of the same hormone. Therefore, these mammals may provide a model for studying clinical populations among humans suffering from sexual arousal deficits such as hypoactive sexual desire disorder.[44]
In one study, almost every mammalian species examined demonstrated a marked increase in a male's testosterone level upon encountering a novel female. P.J. James et al. investigated the role of genotype on such so-called reflexive testosterone increases in male mice. They also concluded that this response is related to the male's initial level of sexual arousal.[45]
In non-human primates it has been suggested that testosterone in puberty stimulates sexual motivation, which allows the primate to increasingly seek out sexual experiences with females and thus creates a sexual preference for females.[46] Some research has also indicated that if testosterone is eliminated in an adult male human or other adult male primate's system, its sexual motivationdecreases, but there is no corresponding decrease in ability to engage in sexual activity (mounting, ejaculating, etc.).[46]
[edit]Male sexual arousal
Higher levels of testosterone were associated with periods of sexual activity within subjects, but between subjects testosterone levels were higher for less sexually active individuals.[47] Men who have sexual encounters with unfamiliar or multiple partners experience large increases of testosterone the morning after.[48]
Men who watch a sexually explicit movie have an average increase of 35% in testosterone, peaking at 60–90 minutes after the end of the film, but no increase is seen in men who watch sexually neutral films.[49] Men who watch sexually explicit films also report increased optimism and decreased exhaustion.[50] Based on previous research that has found a link between relaxation following sexual arousal and testosterone levels,[51]
Testosterone increases in men who engage in brief conversations with women. This result was seen in heterosexual men who had engaged in sexual activity in the 6 months prior to the study. The increase in T levels was associated with the amount of “courtship” behaviours that the men exhibited.[52]
Men’s levels of testosterone, a hormone known to affect men’s mating behaviour, changes depending on whether they are exposed to an ovulating or nonovulating woman’s body odour. Men who are exposed to scents of ovulating women maintained a stable testosterone level that was higher than the testosterone level of men exposed to nonovulation cues. Testosterone levels and sexual arousal in men are heavily aware of hormone cycles in females.[53] This may be linked to the ovulatory shift hypothesis,[54] where males are adapted to respond to the ovulation cycles of females by sensing when they are most fertile and whereby females look for preferred male mates when they are the most fertile; both actions may be driven by hormones.
In a 1991 study, males were exposed to either visual or auditory erotic stimuli and asked to complete a cognitive task, where the number of errors on the task indicated how distracted the participant was by the stimuli. It concluded that men with lower thresholds for sexual arousal have a greater likelihood to attend to sexual information and that testosterone may have an impact by enhancing their attention to the relevant stimuli.[55]
Sperm competition theory: Testosterone levels are shown to increase as a response to previously neutral stimuli when conditioned to become sexual in male rats.[56] This reaction engages penile reflexes (such as erection and ejaculation) that aid in sperm competition when more than one male is present in mating encounters, allowing for more production of successful sperm and a higher chance of reproduction.
[edit]Female sexual arousal
Androgens may modulate the physiology of vaginal tissue and contribute to female genital sexual arousal.[57]
Women’s levels of testosterone are higher when measured pre-intercourse vs pre-cuddling, as well as post-intercourse vs post-cuddling.[58]
López, Hay, and Conklin (2009) found that women who are non-pill users experience a significant increase in testosterone levels in response to viewing a video of an attractive man courting a young woman. This was in comparison with the control conditions.[41]
When females have a higher baseline level of testosterone, they had higher increases in sexual arousal levels but smaller increases in testosterone, indicating a ceiling effect on testosterone levels in females. Sexual thoughts also change the level of testosterone but not level of cortisol in the female body, and that hormonal contraceptives may have an impact on the variation in testosterone response to sexual thoughts.[59]
Van Anders and Dunn (2009) also studied the link between testosterone and orgasms in women, and found a correlation between high T levels and positive orgasm experience. This occurred in both the partnered and solitary context of orgasm.[41]
There is a time lag effect when testosterone is administered, on genital arousal in women. In addition, a continuous increase in vaginal sexual arousal may result in higher genital sensations and sexual appetitive behaviors.[60]
Testosterone may prove to be an effective treatment in female sexual arousal disorders.[61] There is no current androgen preparation or for the treatment of androgen insufficiency approved by the FDA at this point in time, but it has been used off-label to treat low libido and sexual dysfunction in older women. Testosterone may be a treatment for postmenopausal women as long as they are effectively estrogenized.[61]

[edit]Behaviour and personality

Testosterone levels play a major role in risk-taking during financial decisions.[62][63]
The administration of testosterone makes men selfish and more likely to punish others for being selfish towards them.[64]

[edit]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;[13] the enzyme 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.[65]
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.[66] 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 (approx. 15% less).[67]
A study conducted in 1996 found no immediate short term effects on mood or behavior from the administration of supraphysiologicdoses of testosterone for 10 weeks on 43 healthy men.[19] Another study found a correlation between testosterone and risk tolerance in career choice among women.[68]
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,[69][70] 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,[71]where both hypo- and hypersecretion (deficient- and excessive-secretion) of circulating androgens have negative effects on cognition and cognitively modulated aggressivity, as detailed above.[citation needed]
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.[citation needed] 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 disorders and aggressive behaviour,[citation needed]with eugonadal/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.[72][73]

[edit]Aggression and criminality

See also: Aggression#Testosterone and biosocial criminology
The "evolutionary neuroandrogenic theory" focuses on the hormone testosterone as a factor influencing aggression and criminality and being evolutionary beneficial during certain forms of competition. In most species, males are more aggressive than females. Castration of males usually has a pacifying effect on their aggressive behavior. In humans, males engage in crime and especially violent crime more than females. The involvement in crime usually rises in the early teens to mid teens which happen at the same time as testosterone levels rise. Research on the relationship between testosterone and aggression is difficult since the only reliable measurement of brain testosterone is by a lumbar puncture which is not done for research purposes. Studies therefore have often instead used more unreliable measurements from blood or saliva. Most studies support a link between adult criminality and testosterone although the relationship is modest if examined separately for each sex. Nearly all studies of juvenile delinquency and testosterone are not significant. Most studies have also found testosterone to be associated with behaviors or personality traits linked with criminality such as antisocial behavior and alcoholism. Many studies have also been done on the relationship between more general aggressive behavior/feelings and testosterone. About half the studies have found a relationship and about half no relationship.[74]
The testosterone derivative estradiol is known to correlate with aggression in male mice.[75] Moreover, the conversion of testosterone to estradiol regulates male aggression in sparrows during breeding season.[76]

[edit]Ethnic differences

Different ethnic groups have different incidences of prostate cancer. 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.[77][78][79]

[edit]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 hypogonadism. 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 reducinginfertility, 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).[80] Decline of testosterone production with age has led to interest in androgen replacement therapy.[81]
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.[82] 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 inweight 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.[82]

[edit]Hormone replacement therapy

Main article: Androgen replacement therapy
Testosterone levels decline gradually with age in human beings. The clinical significance of this decrease is debated (see andropause). 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 ofandrogen deficiency and decreased testosterone levels are present."[83] 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 borderline testosterone levels warrant a clinical trial of testosterone."[84]
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.[85] 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.[86] 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.

[edit]Benefits

Appropriate testosterone therapy may improve the management of type 2 diabetes.[87] Low testosterone also brings with it an increased risk for the development of Alzheimer's disease.[72][73] A small trial in 2005 showed mixed results in using testosterone to combat the effects of aging.[88]
Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking.[89]

[edit]Adverse effects

Exogenous testosterone supplementation comes with a number of health risks. Fluoxymesterone 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 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.[90]

[edit]Athletic use

Testosterone can be used by an athlete in order to improve performance, but it 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. Supplement of the hormone results in lower metabolic production via the Farquharson phenomenon, creating long term dependence for improved performance level.[citation needed]
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), prohibitions of anabolic steroid use were renewed or strengthened by many sports organizations. Testosterone and other anabolic steroids were designated a "controlled substance" by the United States Congress in 1990, with the Anabolic Steroid Control Act.[91] 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.

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