Testosterone

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TestosteronePubchem(6013) is a steroid hormone from the androgen group. In mammals, testosterone is primarily secreted in the testes 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.Its production is stimulated by LUTEINIZING HORMONE from the PITUITARY GLAND. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to DIHYDROTESTOSTERONE or ESTRADIOL.

In both men and women, testosterone plays a key role in health and well-being as well as in sexual functioning. Examples include enhanced libido, increased energy, increased production of red blood cells and protection against osteoporosis. On average, an adult human male body produces about forty to sixty times more testosterone than an adult female body, but females are, from a behavioral perspective (rather than from an anatomical or biological perspective), more sensitive to the hormone.<ref>James McBride Dabbs, 2000</ref> However the overall ranges for male and female are very wide, such that the ranges actually overlap at the low end and high end respectively.

Contents

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 Berthold (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 wellbeing were markedly restored but, predictably, the effects were transient (and likely based on placebo), 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 20mg of a substance from a supply of 40 pounds of bovine testicles that, when administered to castrated roosters, pigs and rats, remasculinized them.<ref>Gallagher and Koch, 1929.</ref> 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 1930’s.

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)" by Karoly Gyula David, E. Dingemanse, J. Freud and Ernst Laqueur. 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 (1903–1995).

The chemical synthesis of testosterone was achieved in August that year, when Butenandt and G. Hanisch published a paper describing "A Method for Preparing Testosterone from Cholesterol." Only a week later, the Ciba group in Zurich, Leopold Ruzicka (1887–1976) and A. Wettstein, announced a patent application in a paper "On the Artificial Preparation of the Testicular Hormone Testosterone (Androsten-3-one-17-ol)." These independent partial syntheses of testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939 Nobel Prize in Chemistry.<ref>Hoberman and Yesalis 1995, Freeman et al. 2001.</ref> Testosterone was identified as 17β-hydroxandrost-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 Charles Kenyon’s group<ref>Kenyon et al. 1940.</ref> 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",<ref>Schwarz et al. 1999.</ref> 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 wellbeing.<ref>deKruif, 1945.</ref>

KEGG Pathway(C00535,D00075)

  • Androgen and estrogen metabolism
  • Prostate cancer

Activity Androgen

List of PDB files having Testosterone as a Ligand:
MMDB ID PDB ID Reference
15896 1I37 Sack JS, Kish KF, Wang C, Attar RM, Kiefer SE, An Y, Wu GY, Scheffler JE, Salvati ME, Krystek SR Jr, Weinmann R, Einspahr HMCrystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosteroneProc. Natl. Acad. Sci. U. S. A. v98, p.4904-4909
15897 1I38 Sack JS, Kish KF, Wang C, Attar RM, Kiefer SE, An Y, Wu GY, Scheffler JE, Salvati ME, Krystek SR Jr, Weinmann R, Einspahr HMCrystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosteroneProc. Natl. Acad. Sci. U. S. A. v98, p.4904-4909
18740 1I9J Valjakka J, Takkinenz K, Teerinen T, Soderlund H, Rouvinen JStructural insights into steroid hormone binding: the crystal structure of a recombinant anti-testosterone Fab fragment in free and testosterone-bound formsJ. Biol. Chem. v277, p.4183-4190
19484 1J96 Nahoum V, Gangloff A, Legrand P, Zhu DW, Cantin L, Zhorov BS, Luu-The V, Labrie F, Breton R, Lin SXStructure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolutionJ. Biol. Chem. v276, p.42091-42098
30244 1Q13 Couture JF, Legrand P, Cantin L, Labrie F, Luu-The V, Breton RLoop relaxation, a mechanism that explains the reduced specificity of rabbit 20alpha-hydroxysteroid dehydrogenase, a member of the aldo-keto reductase superfamilyJ. Mol. Biol. v339, p.89-102
30428 1VPO Valjakka J, Hemminki A, Niemi S, Soderlund H, Takkinen K, Rouvinen JCrystal structure of an in vitro affinity- and specificity-matured anti-testosterone Fab in complex with testosterone. Improved affinity results from small structural changes within the variable domainsJ. Biol. Chem. v277, p.44021-44027
54139 2Q7I Askew EB, Gampe RT Jr, Stanley TB, Faggart JL, Wilson EMModulation of androgen receptor activation function 2 by testosterone and dihydrotestosteroneJ. Biol. Chem. v282, p.25801-25816
54140 2Q7J Askew EB, Gampe RT Jr, Stanley TB, Faggart JL, Wilson EMModulation of androgen receptor activation function 2 by testosterone and dihydrotestosteroneJ. Biol. Chem. v282, p.25801-25816
54141 2Q7K Askew EB, Gampe RT Jr, Stanley TB, Faggart JL, Wilson EMModulation of androgen receptor activation function 2 by testosterone and dihydrotestosteroneJ. Biol. Chem. v282, p.25801-25816
54142 2Q7L Askew EB, Gampe RT Jr, Stanley TB, Faggart JL, Wilson EMModulation of androgen receptor activation function 2 by testosterone and dihydrotestosteroneJ. Biol. Chem. v282, p.25801-25816
6729 1AFS Bennett MJ, Albert RH, Jez JM, Ma H, Penning TM, Lewis MSteroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol dehydrogenaseStructure v5, p.799-812
Physiochemical properties of Testosterone:
Physical Property Value Units Temp (deg C) Source
Melting Point 155 deg C EXP
log P (octanol-water) 3.32 (none) EXP
Water Solubility 23.4 mg/L 25 EXP
Vapor Pressure 2.23E-08 mm Hg 25 EST
Henry's Law Constant 3.53E-09 atm-m3/mole 25 EST
Atmospheric OH Rate Constant 1.07E-10 cm3/molecule-sec 25 EST
Toxicity:
Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
mammal (species unspecified) LD50 oral > 5gm/kg (5000mg/kg) Toksikologicheskii Vestnik. Vol. (2), Pg. 6, 1996.
rat LDLo intraperitoneal 326mg/kg (326mg/kg) LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES Proceedings of the Society for Experimental Biology and Medicine. Vol. 46, Pg. 116, 1941.

Production

Natural

Image:Steroidogenesis.svg
Human steroidogenesis, showing testosterone near bottom.

Like other steroid hormones, testosterone is derived from cholesterol. The largest amounts of testosterone 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 cells. The male generative glands also contain Sertoli cells which require testosterone for spermatogenesis. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein, sex hormone binding globulin (SHBG).

Artificial

Testosterone is synthesizable in almost unlimited quantities. Furthermore, there are two possible modifications on it, giving it further abilities. First, it can be esterified, permitting a long-lasting effect when injected into the body. Second, it can be alkylated, permitting oral intake instead of injection.

Esterification

The second importance of the hydroxyl side chain at the C-17 position is that it can not only be esterified, but it can also be alkylated (by Alkylation permits oral steroids, substitution of an ethyl or methyl group for the hydroxyl group). the so-called “17-aa” or alkylated family of androgens such as methyl testosterone, which can be taken up by the digestive tract, and so be easily administered in pill form.

Virilizing and effects on humans

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

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.

Prenatal androgen effects

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

Early infancy androgen effects

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.Template:Fact

Early postnatal effects

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

Advanced postnatal effects

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.

Adult testosterone effects

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.

  • Libido and clitoral engorgement/penile erection frequency.
  • Mental and physical energy
  • The most recent and reliable studies have shown that testosterone does not cause Prostate cancer, but that it can increase the rate of spread of any existing prostate cancer.Template:Fact Recent studies have also shown its importance in maintaining cardio vascular health. Template:Fact
  • Increase eumelanin and reduce pheomelaninTemplate:Fact

Testosterone regulates the population of thromboxane A2 receptors on megakaryocytes and platelets and hence platelet aggregation in humans ( Ajayi and Halushka 2005, Ajayi et al 1995)[8,9].

Effects on the brain

As testosterone affects the entire body (often by enlarging; men have bigger hearts, lungs, liver, etc.), the brain is also affected by this "sexual" advancement; the enzyme aromatase converts testosterone into estradiol that is responsible for masculinization of the brain in a male fetus.

There are some differences in a male and female brain (the result of different testosterone levels). A clear difference is the size: the male human brain is, on average, larger; however, in females (who generally do not have as high testosterone levels) the corpus callosum is proportionally larger. This means that the effect of testosterone is a greater overall brain volume, but a decreased connection between the hemispheres.<ref name="Mark Solms & Oliver Turnbull"> Solms and Turnbull 2002.</ref>

A study conducted in 1996 found no effects on mood or behavior from the administration of supraphysiologic doses of testosterone for 10 weeks to healthy men.<ref>Bhasin S, Storer TW, Berman N, et al</ref>

The literature suggests that attention, memory, and spatial ability are key cognitive functions affected by testosterone in humans, though the literature is rather sparse. Preliminary evidence suggests that low testosterone levels may be a risk factor for cognitive decline and possibly for dementia of the Alzheimer’s type,<ref>e.g., Moffat et al, 2005; Hogervorst et al 2005.</ref> 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,<ref>e.g., Moffat and Hampson, 1996.</ref> where both hypo- and hypersecretion 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 hypergonadal 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 disorders 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 consequence of this is an increased risk for the development of Alzheimer’s Disease (Pike et al, 2006, Rosario 2004).

Mechanism

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.

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 T, so that its androgenic potency is about 2.5 times that of T.Template:Fact 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. It is important to note that if there is a 5-alpha reductase deficiency, the body (of a human) will continue growing into a female with testicles.

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 mammals, 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.

Therapeutic use

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,<ref>Template:Cite web</ref> buccal,<ref>Template:Cite web</ref> transdermal skin patches, and transdermal creams or gels.<ref>Template:Cite web and Template:Cite web</ref> In the pipeline are "roll on" methods and nasal sprays.

Indications

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

However, over the years, as with every hormone, testosterone or other anabolic steroids has also been given for many other conditions and purposes besides replacement, with variable success but higher rates of side effects or problems. Examples include infertility, lack of libido or erectile dysfunction, osteoporosis, penile enlargement, height growth, bone marrow stimulation and reversal of anemia, and even appetite stimulation. By the late 1940s testosterone was being touted as an anti-aging wonder drug (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 transmen as part of the hormone replacement therapy, with a "target level" of the normal male testosterone level. Like-wise, transwomen are sometimes prescribed 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 women may be controlled by hair-reduction strategies, acne prevention, etc.

There is a myth that exogenous testosterone can more or less definitively be used for male birth control. However, the vast majority of physicians will agree that to prescribe exogenous testosterone for this purpose is inappropriate. But, perhaps more important, many men found this, in first-hand experience, to be untrue or at least, unreliable.

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 which 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). That said there are many men who have complained of long lasting or permanent adverse effects resulting from the use of finasteride and Dr Eugene Shippen has spoken for many years of finasteride causing a difficult to treat form of hypogonadism in some men.).

Adverse effects

Exogenous testosterone supplementation comes with a number of health risks. Fluoxymesterone and methyltestosterone are synthetic derivatives of testosterone. In 2006 it was reported that women taking Estratest, a combination pill including estrogen and methyltestosterone, were at considerably heightened risk of breast cancer.Template:Fact That said 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. One adverse effect that many men complain of is that of the development of gynecomastia (breasts), but this is something that can be prevented by appropriate choice and dosing of medication, and, in required cases, the use of ancillary medications that help lower SHBG or estradiol. Another side-effect is having difficulty urinating.

Athletic use

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 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.<ref>Template:Cite web</ref> The levels of testosterone abused in sport greatly exceed the quantities of the steroid that are prescribed for medical use in hypogonadism. It is the supraphysiological doses and ultra high levels of testosterone that bring with it many undesirable effects and potential long term adverse health effects. Coupled with the nature of cheating in sport, this 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.

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."<ref>Template:Cite web</ref>

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 300 to 400 ng/dl from a morning sample Template:Vague are generally considered low. Template:Fact 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. Template:Fact Therefore a value of 300 ng/dl might be normal for a 65-year-old male, but not normal for a 30-year-old. Template:Fact 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 Template:Fact 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 which can require venipuncture in order to treat, exacerbation of sleep apnea and acceleration of pre-existing prostate cancer growth. Exogenous testosterone also causes suppression of spermatogenesis and can lead to infertility.<ref name="Lancet">World Health Organisation (1990), The Lancet.</ref> 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.

Appropriate testosterone therapy can prevent or reduce the likelihood of osteoporosis, type 2 diabetes, cardio-vascular disease (CVD), obesity, depression and anxiety and the statistical risk of early mortality. Low testosterone also brings with it an increased risk for the development of Alzheimer’s Disease (Pike et al, 2006, Rosario 2004).

Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking. Many caution against embracing testosterone replacement, whilst others embrace the advantages that the steroid seems to offer.

See also

Notes

Unknown extension tag "references"

References

Ajayi AAL, Mathur R, Halushka PV. Testosterone increases platelet TXA2 receptor density and aggregation responses (1995). Circulation 91 : 2742-7.

Ajayi AAL, Halushka PV. Castration reduces platelet TXA2 receptor density and aggregability (2005). QJM 98 : 349-57.

External links

Template:Hormones Template:Sex hormones Template:Anabolic steroids

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