Testosterone (transdermal): Difference between revisions

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{{Drugbox|
{{DrugProjectFormSinglePage
|IUPAC_name = (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,1
|authorTag={{SS}}:{{AV}}
6,17-dodecahydrocyclopenta[a]phenanthren-3-one
|genericName=Testosterone
| image=Testosterone structure.png
|aOrAn=an
| width=200px
|drugClass=[[androgen]]
| smiles=C[C@]43CCC(=O)\C=C4\CC[C@@H]1[C@@H]3CC[C@]2(C)[C@@H](O)CC[C@@H]12
|indicationType=treatment
| CAS_number=58-22-0
|indication=[[hypogonadism|primary hypogonadism]], and [[hypogonadotropic hypogonadism]]
| ATC_prefix=G03
|adverseReactions=[[acne]], scab of skin, nasal, [[gynecomastia]], oral irritation, [[headache]], [[Prostatomegaly|large prostate]], [[PSA|raised prostate specific antigen]], [[bronchitis]], [[discomfort]], [[epistaxis]], [[nasal discharge]], [[nasopharyngitis]], sense of smell altered, [[sinusitis]], and [[upper respiratory infection]]
| ATC_suffix=BA03
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
| ATC_supplemental=
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
| PubChem=6013
|fdaLIADAdult=<h4>Replacement Therapy in Adult Males for Conditions Associated with a Deficiency or Absence of Endogenous Testosterone</h4>
| DrugBank=
 
| C=19 | H=28 | O=2
* Dosing information
| molecular_weight = 288.43
:* Recommended starting dose: '''4 mg/day (not two 2 mg/day systems) applied nightly for 24 hours, 4 mg PO qd. To ensure proper dosing, approximately 2 weeks after starting therapy, the early morning serum testosterone concentration should be measured following system application the previous evening. Serum concentrations outside the range of 400 - 930 ng/dL require increasing the daily dose to '''6 mg''' (i.e., one '''4 mg/day''' and one '''2 mg/day''' system) or decreasing the daily dose to '''2 mg''',maintaining nightly application.
| bioavailability= low (due to extensive [[First pass effect|first pass metabolism]])
 
| metabolism = [[Liver]], [[Testis]] and [[Prostate]]
:* Patients currently maintained on testosterone 2.5 mg/day, 5 mg/day, and 7.5 mg/day may be switched to the 2 mg/day, 4 mg/day, and 6 mg/day dosage using the following schema:
| elimination_half-life= 2-4 hours
::* Patients using '''2.5 mg daily''' may be switched to '''2 mg/day''' systems at the next scheduled dose.
| excretion =  [[Urine]] (90%), feces (6%)
::* Patients using '''5 mg daily''' may be switched to '''4 mg/day''' systems at the next scheduled dose.
| pregnancy_category = X ([[United States|USA]]), [[Teratogen]]ic effects
::* Patients using '''7.5 mg daily''' may be switched to '''6 mg''' (2 mg/day and 4 mg/day systems) at the next scheduled dose.
| legal_status = Schedule III ([[Controlled Substances Act|USA]])<br />Schedule IV ([[Controlled Drugs and Substances Act|Canada]])
:* To ensure proper dosing, approximately 2 weeks after switching therapy, the early morning serum testosterone concentration should be measured following system application the previous evening.
| routes_of_administration=Intramuscular injection, transdermal (cream, gel, or patch), sub-'Q' pellet
:* The adhesive side of the testosterone system should be applied to a clean, dry area of the skin on the back, abdomen, upper arms, or thighs. Avoid application over bony prominences or on a part of the body that may be subject to prolonged pressure during sleep or sitting (e.g., the deltoid region of the upper arm, the [[greater trochanter]] of the [[femur]], and the [[ischial tuberosity]]). DO NOT APPLY TO THE SCROTUM. The sites of application should be rotated, with an interval of 7 days between applications to the same site. The area selected should not be oily, damaged, or irritated.
| melting_point=155-156
:* The system should be applied immediately after opening the pouch and removing the protective release liner. The system should be pressed firmly in place, making sure there is good contact with the skin, especially around the edges.
| specific_rotation=+110,2°
:* The patient should avoid swimming, showering, or washing the administration site for a minimum of 3 hours after application.
| sec_combustion=−11080 kJ/mol
:* Mild skin irritation may be ameliorated by treatment of the affected skin with over-the-counter topical [[hydrocortisone]] cream applied after system removal. Applying a small amount of 0.1% [[triamcinolone]] acetonide cream to the skin under the central drug reservoir of the testosterone system has been shown to reduce the incidence and severity of skin irritation.
}}
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Testosterone in adult patients.
{{SI}}
|offLabelAdultNoGuideSupport=<h4>Osteoporosis, Male</h4>
__NOTOC__
 
{{CMG}}
* Dosing information
:* ''' 5 to 10 mg/day'''<ref name="pmid11422108">{{cite journal| author=Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G et al.| title=Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. | journal=Clin Endocrinol (Oxf) | year= 2001 | volume= 54 | issue= 6 | pages= 739-50 | pmid=11422108 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11422108  }} </ref>
 
<h4>Weight Gain</h4>
 
* Dosing information
:* '''150 and 300 mcg/day''<ref name="pmid'9709937">{{cite journal| author=Miller K, Corcoran C, Armstrong C, Caramelli K, Anderson E, Cotton D et al.| title=Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study. | journal=J Clin Endocrinol Metab | year= 1998 | volume= 83 | issue= 8 | pages= 2717-25 | pmid='9709937 | doi=10.1210/jcem.83.8.5051 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9709937  }} </ref>
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Testosterone in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Testosterone in pediatric patients.
|contraindications=* Testosterone is contraindicated in men with [[carcinoma]] of the breast or known or suspected [[carcinoma]] of the prostate.
* Testosterone is contraindicated in women who are, or who may become pregnant, or who are [[breastfeeding]]. Testosterone may cause fetal harm when administered to a pregnant woman. Testosterone may cause serious adverse reactions in nursing infants. If a pregnant woman is exposed to testosterone, she should be apprised of the potential hazard to the fetus.
|warnings=====Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer====
 
Monitor patients with [[benign prostatic hyperplasia]] ([[BPH]]) for worsening of signs and symptoms of [[BPH]].
Patients treated with [[androgens]] may be at increased risk for [[prostate cancer]]. Evaluate patients for [[prostate cancer]] prior to initiating treatment. It is appropriate to re-evaluate patients 3 to 6 months after initiation of treatment, and then in accordance with [[prostate cancer]] screening practices.
 
====Polycythemia====
 
Increases in [[hematocrit]], reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check [[hematocrit]] prior to initiating testosterone treatment. It is appropriate to re-evaluate the [[hematocrit]] 3 to 6 months after starting testosterone treatment, and then monitor annually. Discontinue testosterone therapy if the [[hematocrit]] becomes elevated. Testosterone therapy may be restarted when the [[hematocrit]] decreases to an acceptable level. An increase in red blood cell mass may increase the risk of [[thromboembolism|thromboembolic events]].
 
====Venous Thromboembolism====
 
There have been post marketing reports of venous [[thromboembolism|thromboembolic events]], including [[deep vein thrombosis]] ([[DVT]]) and [[pulmonary embolism]] ([[PE]]), in patients using testosterone products such as testosterone. Evaluate patients who report symptoms of pain, [[edema]], warmth and [[erythema]] in the lower extremity for [[DVT]] and those who present with acute [[shortness of breath]] for [[PE]]. If a venous [[thromboembolism|thromboembolic events]] is suspected, discontinue treatment with testosterone and initiate appropriate workup and management.
 
====Use in Women and Children====
 
Women and children should not use testosterone. Use in women and children has not been studied with testosterone.
Due to lack of controlled studies in women and potential virilizing effects, testosterone is not indicated for use in women and children.
 
====Potential for Adverse Effects on Spermatogenesis====
 
At large doses of exogenous [[androgens]], including testosterone, [[spermatogenesis]] may be suppressed through feedback inhibition of pituitary [[follicle-stimulating hormone]] ([[FSH]]) that could lead to adverse effects on semen parameters including reduction of sperm count.
 
====Hepatic Adverse Effects====
 
Prolonged use of high doses of orally active 17-alpha-alkyl androgens ([[methyltestosterone]]) has been associated with serious hepatic adverse effects ([[peliosis hepatis]], hepatic neoplasms, [[hepatitis|cholestatic hepatitis]], and [[jaundice]]). [[Peliosis hepatis]] can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple [[hepatic adenomas]]. Testosterone is not known to cause these adverse effects.


==Overview==
====Edema====
'''Testosterone''' is a [[steroid hormone]] from the [[androgen]] group. Testosterone is primarily secreted in the [[testis|testes]] of males and the [[ovaries]] of females, although small amounts are also secreted by the [[adrenal gland]]s.  It is the principal [[male]] sex [[hormone]] and an [[anabolic steroid]]. In both males and females, it plays key roles in health and well-being.  Examples include enhanced [[libido]], energy, [[immune function]], and protection against [[osteoporosis]]. On average, an adult [[human]] male body produces about eight to ten times more testosterone than an adult female body.<ref>James McBride Dabbs, 2000</ref> Testosterone is found in numerous animals.


==History==
[[Androgens]], including testosterone, may promote retention of sodium and water. [[Edema]], with or without [[congestive heart failure]], may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease.
Testicular action was linked to circulating blood fractions &mdash; now understood to be a family of androgenic hormones &mdash; in the early work on castration and testicular transplantation in fowl by Arnold Bethold (1803&ndash;1861). Research on the action of testosterone received a brief boost in 1889, when the Harvard professor Charles-Edouard Brown-Séquard (1817&ndash;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 &mdash; the Chicago stockyards &mdash; 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 bull 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 clearly not feasible until three European pharmaceutical giants &mdash; [[Schering]] (Berlin, Germany), Organon (Oss, Netherlands) and [[Ciba]] (Basel, Switzerland) &mdash; began full-scale steroid research and development programs in the 1930’s.
====Gynecomastia====


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&ndash;1995).
[[Gynecomastia]] may develop and persist in patients being treated with [[androgens]], including testosterone, for [[hypogonadism]].


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&ndash;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.
====Sleep Apnea====


The partial synthesis in the 1930’s 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 1930’s to the 1950’s 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 &mdash; testosterone &mdash; or rather family of compounds (for many derivatives were developed in the 1940’s, 50’s and 60’s), was a potent multiplier of muscle, strength, and wellbeing.<ref>deKruif, 1945.</ref>
The treatment of hypogonadal men with testosterone may potentiate [[sleep apnea]] in some patients, especially those with risk factors such as [[obesity]] and [[chronic lung disease.]]


==Production==
====Lipids====
===Natural===
Like other [[steroid]] hormones, testosterone is derived from [[cholesterol]]. The largest amounts of testosterone are produced by the [[testis|testes]] in men. It is also synthesized in far smaller quantities in women by the [[thecal cells]] of the [[ovary|ovaries]], by the [[placenta]], as well as by the [[zona reticularis]] of the [[adrenal gland|adrenal cortex]] in both sexes. 


In the [[testes]], testosterone is produced by the [[Leydig cell]]s. The male [[gonads|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).
Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy.


===Artificial===
====Hypercalcemia====
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 ====
[[Androgens]], including testosterone, should be used with caution in cancer patients at risk of [[hypercalcemia]] (and associated [[hypercalciuria]]). Regular monitoring of serum calcium concentrations is recommended in these patients.
The C-17 hydroxyl group testosterone can 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 with testosterone 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.


====Alkylation====
====Decreased Thyroxine-Binding Globulin====
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 substitution of an ethyl or methyl group for the hydroxyl group). Alkylation permits oral steroids, the so-called “17-aa” or alkylated family of androgens such as methyltestosterone, which can be taken up by the digestive tract, and so be easily administered in pill form.


==Virilizing and anabolic effects on humans==
[[Androgens]], including testosterone, may decrease concentrations of [[thyroxine]]-binding globulins, resulting in decreased total T4 serum concentration and increased resin uptake of T3 and [[T4]]. Free thyroid hormone concentration remains unchanged and there is no clinical evidence of thyroid dysfunction.
In general, [[androgens]] promote [[protein synthesis]] and growth of those tissues with [[androgen receptors]]. Testosterone effects can be classified as virilizing and anabolic effects, although the distinction is somewhat artificial, as many of the effects can be considered both.  


* ''Anabolic effects'' include growth of [[muscle mass]] and strength, increased [[bone density]] and strength, and stimulation of linear growth and [[bone maturation]].
====Magnetic Resonance Imaging MRI====
* ''Virilizing effects'' include [[maturation]] of the [[sex organs]], particularly the [[penis]] and the formation of the [[scrotum]] in unborn children, and after birth (usually at [[puberty]]) a deepening of the voice, growth of the beard and [[axillary hair]]. Many of these fall into the category of male [[secondary sex characteristic]]s.


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.
Skin burns have been reported at the application site in patients wearing an aluminized transdermal system during a [[magnetic resonance imaging scan]] ([[MRI]]). Because testosterone contains aluminum, it is recommended to remove the system before undergoing an [[MRI]].
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Table 1 shows the adverse reactions that were reported by > 3% of 36 hypogonadal men who were treated with testosterone 2 mg/day, 4 mg/day, or 6 mg/day for 28 days. Of note, all hypogonadal men studied had been stable users of topical testosterone replacement products prior to the study and there was no washout period between therapies. Furthermore, there was only one subject titrated to 6 mg/day and he withdrew from the study prematurely.  


===Prenatal androgen effects===
[[File:Testosterone_adverse_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Most of the ''prenatal androgen effects'' occur between 7 and 12 weeks of gestation.
*Genital virilization (midline fusion, [[phallus|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 vesicle]]s


===Early infancy androgen effects===
Other less common adverse reactions reported by < 3% of patients included: application site [[erythema]], application site exfoliation, [[chills]], [[diarrhea]], [[fatigue]], [[GERD|gastroesophageal reflux disease]], [[hemarthrosis]], [[hematuria]], [[headache]], [[polyuria]], and [[prostatitis]]. The overall incidence of application site reactions of any kind was 28% (10 subjects with 13 adverse reactions).
''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.
No serious adverse reactions to testosterone 2 mg/day and 4 mg/day were reported during the clinical trial.
Table 2 shows the adverse reactions that were reported in > 3% of 122 patients in clinical studies with testosterone dosage strengths of 2.5 mg/day, 5 mg/day, and 7.5 mg/day. The most common adverse reactions reported were application site reactions. Transient mild to moderate erythema was observed at the site of application in the majority of patients at some time during treatment. The overall incidence of application site reactions of any kind was 48% (59 subjects with 107 adverse reactions).


===Early postnatal effects===
[[File:Testosterone_adverse_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
''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 vulgaris|acne]]
*[[Pubarche]] (appearance of [[pubic hair]])
*[[Axillary hair]]
*[[Growth spurt]], accelerated [[epiphysis|bone maturation]]
*Fine upper lip and sideburn hair


===Advanced postnatal effects===
The following reactions occurred in less than 3% of patients: [[rash]], [[gastrointestinal bleeding]], [[fatigue]], body pain, pelvic pain, [[hypertension]], [[peripheral vascular disease]], [[increased appetite]], accelerated growth, [[anxiety]], [[confusion]], decreased libido, [[paresthesia]], thinking abnormalities, [[vertigo]], [[acne]], bullae at application site, mechanical irritation at application site, [[rash]] at application site, contamination of application site, prostate carcinoma, [[dysuria]], [[hematuria]], [[impotence]], [[urinary incontinence]], [[urinary tract infection]], and testicular abnormalities.
''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.
|postmarketing=The following adverse reactions have been identified during post approval use of testosterone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
*[[Phallic]] enlargement (including [[clitoromegaly]])
*Increased [[libido]] and frequency of [[erection]] or clitoral engorgement
*Pubic hair extends to thighs and up toward [[Navel|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===
====Vascular Disorders:====
''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
*The most recent and reliable studies have shown that testosterone does not cause prostate cancer, but that it can increase the rate of spead of any existing prostate cancer.  Recent studies have also shown its importance in maintaining cardio vascular health.
*Increase [[eumelanin]] and reduce [[pheomelanin]]
*A lack of testosterone can lead to a statistically significant increase in the liklihood of cardio vascular disease (CVD), type 2 diabetes (a third of all me with type 2 diabetes have low testosterone), low testosterone can cause osteoporosis in males.  A lack of testosterone has been shown to be associated with increased adipose fat, obesity and a difficulty in losing excess weight and has been strongly associated with depression.  Most alarming is the recent evidence/studies that have shown that a lack of testosterone greatly increase mortality rates in men over 50.


==Effects on the brain==
[[Venous thromboembolism]]
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.
|drugInteractions=====Insulin====


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 do not use testosterone as much) 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 [[Cerebral hemisphere|hemispheres]].<ref name="Mark Solms & Oliver Turnbull"> Solms and Turnbull 2002.</ref>
Changes in [[insulin]] sensitivity or glycemic control may occur in patients treated with [[androgens]]. In diabetic patients, the metabolic effects of [[androgens]] may decrease blood [[glucose]] and, therefore, [[insulin]] requirement.


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.
====Oral Anticoagulants====


A lack of testosterone is strongly linked to depression and anxiety syndromes, when a lack of testosterone and a hypogondal state are the cause of such problems restortion of eugondal status by appropriate testosterone replacement often helps reduce or resolve such conditions.
Changes in [[anticoagulant activity]] may be seen with [[androgens]]. More frequent monitoring of [[INR]] and [[prothrombin time]] is recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.


Contrary to what has been postulated in outdated studies and by certain sections of the media, agressive behaviour is not typically seen in hypogondal men who have their testosterone replaced adequately to the eugonadal/normal range.  In fact aggressive behaviour has 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).
====Corticosteroids====


==Mechanism==
The concurrent use of testosterone with [[ACTH]] or [[corticosteroids]] may result in increased fluid retention and should be monitored, particularly in patients with cardiac, renal or hepatic disease.


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 receptor]]s.
====Triamcinolone====


Free testosterone (T) is transported into the [[cytoplasm]] of target [[tissue]] [[Cell (biology)|cells]], where it can bind to the androgen [[Receptor (biochemistry)|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. 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 [[chromosome|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. It is important to note that if there is a 5-alpha reductase deficiency,<!-- in the womb? during childhood? --> the body (of a human) will ''continue'' growing into a female with testicles.
The topical administration of 0.1% [[triamcinolone]] cream to the skin under the central drug reservoir prior to the application of the testosterone system did not significantly alter transdermal absorption of testosterone; however, the rate of complete adherence was lower.
Pre treatment with [[triamcinolone]] ointment formulation significantly reduced testosterone absorption from the testosterone system.
|FDAPregCat=X
|useInPregnancyFDA=Pregnancy Category X  — Testosterone is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a female fetus to [[androgens]] may result in varying degrees of [[virilization]]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
|useInNursing=Although it is not known how much testosterone transfers into human milk, Testosterone is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Testosterone and other [[androgens]] may adversely affect lactation.
|useInPed=Safety and efficacy of testosterone have not been established in males <18 years of age. Improper use may result in acceleration of bone age and premature closure of [[epiphyses]].
|useInGeri=There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing testosterone to determine whether efficacy in those over 65 years of age differs from younger patients. Additionally, there are insufficient long-term safety data in geriatric patients utilizing testosterone to assess a potential incremental risk of cardiovascular disease and [[prostate cancer]].
|useInRenalImpair=No studies were conducted in patients with [[renal impairment]].
|useInHepaticImpair=No studies were conducted in patients with [[hepatic impairment]].
|overdose=No cases of overdose with testosterone have been reported in clinical trials. There is one report of acute overdosage by injection of testosterone enanthate: testosterone concentrations of up to 11,400 ng/dL were implicated in a cerebrovascular accident. Treatment of overdosage would consist of discontinuation of testosterone together with appropriate symptomatic and supportive care.


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 [[sexual differentiation|differences]] between males and females.
====Controlled Substance====


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 [[epiphysis|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 [[luteinizing hormone|LH]] secretion). In many [[mammal]]s, prenatal or perinatal "masculinization" of the [[sexual dimorphism|sexually dimorphic]] areas of the brain by estradiol derived from testosterone programs later male sexual behavior.
Testosterone contains testosterone, a Schedule III controlled substance under the [[Anabolic Steroids]] Control Act.


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.
====Abuse====


==Therapeutic use==
[[Anabolic steroids]], such as testosterone, are abused. Abuse is often associated with adverse physical and psychological effects.
===Routes of administration===
There are many [[routes of administration]] for testosterone. Forms of testosterone for human administration currently available in North America include injectable (such as testosterone cypionate or testosterone enanthate in oil), oral,<ref>{{cite web
|url = http://google2.fda.gov/search?client=FDA&site=FDA&oe=&lr=&proxystylesheet=FDA&output=xml_no_dtd&getfields=*&q=Andriol&as=GO
|title=Andriol|publisher=Food and Drug Administration}}</ref> buccal,<ref>{{cite web
|url = http://google2.fda.gov/search?client=FDA&site=FDA&oe=&lr=&proxystylesheet=FDA&output=xml_no_dtd&getfields=*&q=Striant&as=GO
|title=Striant|publisher=Food and Drug Administration}}</ref> transdermal skin patches, and transdermal creams or gels.<ref>{{cite web
|url = http://www.fda.gov/medwatch/SAFETY/2003/03SEP_PI/AndroGel_PI.pdf
|title=Androgel|publisher=Food and Drug Administration}} and {{cite web
|url = http://google2.fda.gov/search?client=FDA&site=FDA&oe=&lr=&proxystylesheet=FDA&output=xml_no_dtd&getfields=*&q=Testim.&as=GO
|title=Testim|publisher=Food and Drug Administration}}</ref> In the pipeline are "roll on" methods and nasal sprays.


===Indications===
====Dependence====
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]], [[penis enlargement|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]].
Although drug dependence is not documented in individuals using therapeutic doses of [[anabolic steroids]] for approved indications, dependence is observed in some individuals abusing high doses of [[anabolic steroids]]. In general, anabolic steroid dependence is characterized by any three of the following:
* Taking more drug than intended
* Continued drug use despite medical and social problems
* Significant time spent in obtaining adequate amounts of drug
* Desire for [[anabolic steroids]] when supplies of the drug are interrupted
* Difficulty in discontinuing use of the drug despite desires and attempts to do so
* Experience of [[withdrawal syndrome]] upon discontinuation of [[anabolic steroid]] use
|drugBox={{Drugbox2| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 420412587
| IUPAC_name = (8''R'',9''S'',10''R'',13''S'',14''S'',17''S'')- 17-hydroxy-10,13-dimethyl- 1,2,6,7,8,9,11,12,14,15,16,17- dodecahydrocyclopenta[''a'']phenanthren-3-one
| image = Testosteronstruc.png
| image2 = Testosterone-from-xtal-3D-balls.png


To take advantage of its [[virilizing]] effects, testosterone is often administered to [[female-to-male]] [[transsexual]] men as part of the [[Hormone replacement therapy (trans)|hormone replacement therapy]], with a "target level" of the normal male testosterone level. Like-wise, [[male-to-female]] [[transsexual]] women are sometimes prescribed drugs ([[antiandrogen|anti-androgens]]) to decrease the level of testosterone in the body and allow for the effects of estrogen to develop.
<!--Clinical data-->
| tradename = Androderm, Delatestryl
| Drugs.com = {{drugs.com|monograph|testosterone}}
| pregnancy_US = X
| pregnancy_category =  [[Contraindication|Contraindicated]] due to [[teratogen]]ic effects
| legal_US = Schedule III
| legal_CA = Schedule IV
| licence_US = Testosterone
| legal_status = Rx-only
| routes_of_administration = Intramuscular injection, transdermal (cream, gel, or patch), sub-'Q' pellet
<!--Pharmacokinetic data-->
| bioavailability = Low (due to extensive [[first pass effect|first pass metabolism]])
| metabolism = [[Liver]], [[testis]] and [[prostate]]
| elimination_half-life = 2–4&nbsp;hours
| excretion = [[Urine]] (90%), feces (6%)


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. 
<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 58-22-0
| CAS_supplemental = <br/>{{CAS|57-85-2}} (propionate ester) <!-- Also CAS verified -->
| ATC_prefix = G03
| ATC_suffix = BA03
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 17347
| PubChem = 6013
| IUPHAR_ligand = 2858
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00624
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5791
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3XMK78S47O
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00075
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 386630


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.
<!--Chemical data-->
| C=19 | H=28 | O=2
| molecular_weight = 288.42
| smiles = O=C4\C=C2/[C@]([C@H]1CC[C@@]3([C@@H](O)CC[C@H]3[C@@H]1CC2)C)(C)CC4
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H28O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h11,14-17,21H,3-10H2,1-2H3/t14-,15-,16-,17-,18-,19-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = MUMGGOZAMZWBJJ-DYKIIFRCSA-N
| melting_point = 155
| specific_rotation = +110.2°
| sec_combustion = −11080 kJ/mol
}}
|mechAction=Endogenous [[androgens]], including testosterone and [[dihydrotestosterone]] ([[DHT]]), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of [[prostate]], [[seminal vesicles]], [[penis]] and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement; vocal cord thickening; and alterations in body musculature and fat distribution. Testosterone and [[DHT]] are necessary for the normal development of secondary sex characteristics. Male [[hypogonadism]] results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Signs/symptoms associated with male [[hypogonadism]] include [[erectile dysfunction]] and decreased sexual desire, [[fatigue]] and loss of energy, mood depression, regression of secondary sexual characteristics, and [[osteoporosis]].
Male [[hypogonadism]] has two main etiologies. Primary [[hypogonadism]] is caused by defects of the gonads, such as [[Klinefelter Syndrome]] or [[Leydig cell aplasia]], whereas secondary [[hypogonadism]] is the failure of the [[hypothalamus]] (or pituitary) to produce sufficient gonadotropins ([[FSH]], [[LH]]).
|structure=Testosterone (testosterone transdermal system) is designed to deliver testosterone continuously for 24 hours following application to intact, non-scrotal skin (e.g., back, abdomen, thighs, upper arms).
Two strengths of testosterone are available that deliver approximately 2 mg or 4 mg of testosterone per day.
Testosterone has a central drug delivery reservoir surrounded by a peripheral adhesive area. The testosterone 2 mg/day system has a total contact surface area of 32 cm2 with a 6.0 cm2 central drug delivery reservoir containing 9.7 mg testosterone USP, dissolved in an alcohol-based gel. The testosterone 4 mg/day system has a total contact surface area of 39 cm2 with a 12.0 cm2 central drug delivery reservoir containing 19.5 mg testosterone USP, dissolved in an alcohol-based gel. Testosterone USP is a white, or creamy white crystalline powder or crystals chemically described as 17ß-hydroxyandrost-4-en-3-one.


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 affects 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.]]).
[[File:Testosterone_structure_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


===Adverse effects===
The testosterone systems have six components as shown in Figure 1. Proceeding from the top toward the surface attached to the skin, the system is composed of (1) metallized polyester/Surlyn® (ethylene-methacrylic acid copolymer)/ethylene vinyl acetate backing film with alcohol resistant ink, (2) a drug reservoir of testosterone USP, alcohol USP, [[glycerin]] USP, glycerol monooleate, methyl laurate, sodium hydroxide NF, to adjust pH, and purified water USP, gelled with carbomer copolymer Type B NF, (3) a permeable polyethylene microporous membrane, and (4) a peripheral layer of acrylic adhesive surrounding the central, active drug delivery area of the system. Prior to opening of the system and application to the skin, the central delivery surface of the system is sealed with a peelable laminate disc (5) composed of a five-layer laminate containing polyester/polyesterurethane adhesive/aluminum foil/polyester-urethane adhesive/polyethylene. The disc is attached to and removed with the release liner (6), a silicone-coated polyester film, which is removed before the system can be used.
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]]. 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 hypogondal men. One adverse effect that many men complain of is that of the development of gynecomastia (breasts), 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.


===Athletic use===
[[File:Testosterone_structure_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Testosterone may be administered to an athlete in order to improve performance, and is considered to be a form of [[Doping (sport)|doping]] in most sports. There are several application methods for testosterone, including [[intramuscular injection]]s, [[transdermal|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.  In result muscle fibers become larger and repair faster than the average person's.
The active ingredient in the system is testosterone. The remaining components of the system are pharmacologically inactive.
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>{{cite web
|PD=No specific pharmacodynamic studies were conducted using testosterone.
|url = http://www.ussc.gov/USSCsteroidsreport-0306.pdf#search=%22Anabolic%20Steroid%20Control%20Act%20of%201990%22
|PK=====Absorption====
|title = Anabolic Steroid Control Act| publisher = United States Sentencing Commission|year = 1990}}</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 and a seriously problematic issue in modern sport, particulary given the lengths to which athletes are professional laboratories go to in trying to conceal such abuse from sports regulators.


==Changes during aging==
Testosterone delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate the normal concentration range (300 - 1030 ng/dL) seen in healthy men. Testosterone provides a continuous daily dose of testosterone in a self-contained transdermal system. Following testosterone application, testosterone is continuously absorbed during the 24-hour dosing period with a median (range) Tmax of 8 (4-12) hours.


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>{{cite web
====Distribution====
|url = http://www.aace.com/pub/pdf/guidelines/sexdysguid.pdf
|title = Medical guildelines for clinical practice for the evaluation and treatment of male sexual dysfunction
|publisher = American association of clinical endocrinologists}}</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 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.  
Circulating testosterone is primarily bound in the serum to [[sex hormone-binding globulin]] ([[SHBG]]) and [[albumin]]. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.


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>
====Metabolism====
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 it would seem prevent or reduce the likelihood of osteoporosis, type 2 diabetes, cardvio 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).  
Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are [[estradiol]] and [[dihydrotestosterone]] (DHT).
During steady-state pharmacokinetic studies in hypogonadal men treated with testosterone, the average DHT:T and E2:T ratios were approximately 1:10 and 1:200, respectively.


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.
====Excretion====


==Additional images==
There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and [[sulfuric acid]] conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.
<gallery>
Upon removal of the testosterone systems, serum testosterone concentrations decrease with an apparent half-life of approximately 70 minutes. Hypogonadal concentrations are reached within 24 hours following system removal. There is no accumulation of testosterone during continuous treatment.
Image:Steroidogenesis.gif|[[Steroidogenesis]]
</gallery>


==See also==
====Effect of Showering====
*[[Male]]
*[[Testosterone spray]]


==Notes==
In a two-way crossover study, the effects of showering on the [[pharmacokinetics]] of total testosterone following a single application of testosterone 4 mg/day were assessed in 16 [[hypogonadal]] males. Showering 3 hours after application of testosterone increased Cavg by 0.5% and decreased [[Cmax]] by 0.4% respectively, as compared to not showering. The systemic exposure to testosterone was similar following applications with or without showering 3 hours after application.
{{Reflist|2}}
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====


==References==
Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to [[hepatoma]]. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. Testosterone was negative in the in vitro Ames and in the in vivo mouse micro nucleus assays. The administration of exogenous testosterone has been reported to suppress [[spermatogenesis]] in the rat, dog and non-human primates, which was reversible on cessation of the treatment.
|clinicalStudies=Testosterone 2 mg/day and 4 mg/day were studied in a trial designed to evaluate the use and titration of 2 mg/day and 4 mg/day systems in a clinic setting of 40 men with [[hypogonadism]].  Thirty-eight of the 40 subjects (95%) who were enrolled into the study were white and 2 subjects were African American.  Ten (25%) subjects were hispanic and 30 (75%) were non-hispanic.  Men were between 34 and 76 years of age (mean: 55 years).  Patients had previously been on stable therapy of testosterone 5 mg; Androgel® 2.5 g, 5 g, 7.5 g or 10 g; or Testim® 2.5 g or 5 g daily before switching to testosterone 4 mg/day.
Patients applied an testosterone 4 mg/day system around 10 p.m. once daily for 14 days, and then were titrated up to 6 mg/day or down to 2 mg/day according to a morning serum testosterone concentration obtained at 6 a.m. on Day 8. Out of 36 patients who entered the study, 31 (86%) patients remained on the 4 mg/day dose, 4 (11%) were titrated downward to 2 mg/day, and 1 (3%) was titrated upward to 6 mg/day based on the Day 8 testosterone concentrations. The one patient that was titrated to 6 mg/day discontinued from the study for a non-safety related reason. Of the patients who were receiving testosterone 5 mg/day prior to study entry (n = 11), 10 remained at 4 mg/day after titration, and 1 was titrated down to the 2 mg/day dose.
After a total of 28 days of therapy, 34 of the 35 subjects (97%) had serum testosterone [[Cavg]] within the normal range during the dosing period, with the lower bound of the 95% confidence interval for this estimate being 85% (Table 3).  One subject who received testosterone 4 mg/day treatment had serum testosterone Cavg below 300 ng/dL and none had Cavg concentrations above 1030 ng/dL.  The mean (SD) serum testosterone [[Cmax]] following treatment with the 2 mg/day (N = 4) and 4 mg/day (N = 31) systems was 648 (145) ng/dL and 696 (158) ng/dL, respectively. Table 3 summarizes testosterone Cavg categories by treatment.


* {{cite journal
[[File:Testosterone_clinical studies_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|author=E.R. Freeman, D.A. Bloom, and E.J. McGuire
|title=A brief history of testosterone
|journal=Journal of Urology
|volume=165
|issue=
|pages=371&ndash;373
|year=2001
|pmid= 11176375}}
* {{cite journal
|author=J.M. Hoberman and C.E. Yesalis
|title=The history of synthetic testosterone
|journal=Scientific American
|volume=272
|issue=
|pages=76&ndash;81
|year=1995
|pmid=7817189}}
* {{cite book| author = P.R. Larsen ''et al.'' |title = Williams textbook of endocrinology| edition = 10th edition|publisher = Saunders| year = 2003| isbn =978-0-7216-9184-8}} (Seventh edition by J.D. Wilson and R.H. Williams, 1985, ISBN 072161082X.)
* {{cite journal|author = S.D. Moffat and E. Hampson| title =  A curvilinear relationship between testosterone and spatial cognition in humans: Possible influence of hand preference| journal = Psychoneuroendocrinology|volume = 21|issue = 3| pages = 323&ndash;337|year = 1996}}
* {{cite journal|author = S.D. Moffat, A.B. Zonderman, E.J. Metter ''et al.''| year = 2004| title = Free testosterone and risk for Alzheimer's disease in older men|journal = Neurology|volume = 62| pages = 188&ndash;193}}
* {{cite journal|author = M. Parssinen, U. Kujala, E. Vartiainen, ''et al.''| year= 2000|title = Increased premature mortality of competitive powerlifters suspected to have used anabolic agents| journal = International Journal of Sports Medicine|volume = 21|pages= 225&ndash;227}}
* {{cite journal|author = S. Schwarz, D. Onken, and A. Schubert|title = The steroid story of Jenapharm: From the late 1940s to the early 1970s
|journal = Steroids|volume = 64|year = 1999|pages = 439&ndash;445|url = http://www.ingentaconnect.com/content/els/0039128x/1999/00000064/00000007/art00003|doi = 10.1016/S0039-128X(99)00003-3}}
* {{cite book| author= M. Solms and O. Turnbull| title = The brain and the inner world| publisher = Other Press, New York| year = 2002|isbn = 978-1590510179}}
* {{cite journal | author = World Health Organization Task Force on methods for the regulation of male fertility
|title = Contraceptive efficacy of testosterone-induced azoospermia in normal men| journal = Lancet
|year = 1990 | volume = 336 |pages =955&ndash;959| pmid = 1977002}}


{{Hormones}}
Figure 2 summarizes the pharmacokinetic profiles of total testosterone in 35 patients completing 28 days of testosterone treatment applied as a starting dose of 4 mg/day for the initial 14 days followed by a possible dose titration.
{{Sex hormones}}
{{Anabolic steroids}}


[[File:Testosterone_clinical studies_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
In separate clinical studies using the testosterone 2.5 mg/day system, 1% used 2.5 mg daily, 93% of patients used 5 mg daily, and 6% used 7.5 mg daily. The hormonal effects of testosterone 2.5 mg/day system as a treatment for male [[hypogonadism]] was demonstrated in four open-label trials that included 94 hypogonadal men, ages 15 to 65 years. In these trials, testosterone produced average morning serum testosterone concentrations within the normal reference range in 92% of patients.
|howSupplied=Testosterone (testosterone transdermal system) 2 mg/day.
Each system contains 9.7 mg testosterone USP for delivery of 2 mg of testosterone per day.
Cartons of 60 systems NDC 52544-076-60
Testosterone (testosterone transdermal system) 4 mg/day.
Each system contains 19.5 mg testosterone USP for delivery of 4 mg of testosterone per day.
Cartons of 30 systems NDC 52544-077-30
|storage=Store at 20-25°C (68-77°F). [See USP controlled room temperature.] Apply to skin immediately upon removal from the protective pouch. Do not store outside the pouch provided. Damaged systems should not be used. The drug reservoir may be burst by excessive pressure or heat. Discard systems in household trash in a manner that prevents accidental application or ingestion by children, pets or others.
|fdaPatientInfo=[[File:Testosterone_patient information_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|alcohol=Alcohol-Testosterone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Androderm
* Androgel
* Striant
* Testim
* Testro AQ
* Testopel Pellets
* Axiron
* Fortesta
|lookAlike=Testoderm - Testoderm TTS
Testoderm - Testoderm with Adhesive
Testoderm with Adhesive - Testoderm TTS<ref name="www.ismp.org">{{Cite web  | last =  | first =  | title =https://www.ismp.org | url = https://www.ismp.org | publisher =  | date =  | accessdate = }}</ref>
}}
{{LabelImage
|fileName=Testosteron_label_01.jpg
}}
{{LabelImage
|fileName=Testosteron_label_03.jpg
}}
{{LabelImage
|fileName=Testosteron_label_04.jpg
}}
{{LabelImage
|fileName=Testosteron_panel_01.png
}}
{{LabelImage
|fileName=Testosteron_panel_02.png
}}
{{LabelImage
|fileName=Testosteron_panel_03.png
}}
{{LabelImage
|fileName=Testosteron_panel_04.png
}}


[[Category:Androgens]]
[[Category:Androgens]]
[[Category:Drug]]
[[Category:Erectile dysfunction drugs]]
[[Category:Erectile dysfunction drugs]]
[[Category:Neuroendocrinology]]
[[Category:Neuroendocrinology]]
[[Category:Anabolic steroids]]
[[Category:Anabolic steroids]]
[[Category:Endocrinology]]
[[af:Testosteroon]]
[[ar:تستوستيرون]]
[[cv:Тестостерон]]
[[cs:Testosteron]]
[[da:Testosteron]]
[[de:Testosteron]]
[[es:Testosterona]]
[[eo:Testosterono]]
[[fr:Testostérone]]
[[hr:Testosteron]]
[[id:Testosteron]]
[[it:Testosterone]]
[[he:טסטוסטרון]]
[[ku:Testosteron]]
[[lt:Testosteronas]]
[[nl:Testosteron]]
[[ja:テストステロン]]
[[no:Testosteron]]
[[pl:Testosteron]]
[[pt:Testosterona]]
[[ru:Тестостерон]]
[[simple:Testosterone]]
[[sk:Testosterón]]
[[sr:Тестостерон]]
[[fi:Testosteroni]]
[[sv:Testosteron]]
[[tr:Testosteron]]
[[zh:睾酮]]
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Latest revision as of 08:24, 23 May 2015

Testosterone (transdermal)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]:Aparna Vuppala, M.B.B.S. [3]

Disclaimer

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Overview

Testosterone (transdermal) is an androgen that is FDA approved for the treatment of primary hypogonadism, and hypogonadotropic hypogonadism. Common adverse reactions include acne, scab of skin, nasal, gynecomastia, oral irritation, headache, large prostate, raised prostate specific antigen, bronchitis, discomfort, epistaxis, nasal discharge, nasopharyngitis, sense of smell altered, sinusitis, and upper respiratory infection.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Replacement Therapy in Adult Males for Conditions Associated with a Deficiency or Absence of Endogenous Testosterone

  • Dosing information
  • Recommended starting dose: 4 mg/day (not two 2 mg/day systems) applied nightly for 24 hours, 4 mg PO qd. To ensure proper dosing, approximately 2 weeks after starting therapy, the early morning serum testosterone concentration should be measured following system application the previous evening. Serum concentrations outside the range of 400 - 930 ng/dL require increasing the daily dose to 6 mg (i.e., one 4 mg/day and one 2 mg/day system) or decreasing the daily dose to 2 mg,maintaining nightly application.
  • Patients currently maintained on testosterone 2.5 mg/day, 5 mg/day, and 7.5 mg/day may be switched to the 2 mg/day, 4 mg/day, and 6 mg/day dosage using the following schema:
  • Patients using 2.5 mg daily may be switched to 2 mg/day systems at the next scheduled dose.
  • Patients using 5 mg daily may be switched to 4 mg/day systems at the next scheduled dose.
  • Patients using 7.5 mg daily may be switched to 6 mg (2 mg/day and 4 mg/day systems) at the next scheduled dose.
  • To ensure proper dosing, approximately 2 weeks after switching therapy, the early morning serum testosterone concentration should be measured following system application the previous evening.
  • The adhesive side of the testosterone system should be applied to a clean, dry area of the skin on the back, abdomen, upper arms, or thighs. Avoid application over bony prominences or on a part of the body that may be subject to prolonged pressure during sleep or sitting (e.g., the deltoid region of the upper arm, the greater trochanter of the femur, and the ischial tuberosity). DO NOT APPLY TO THE SCROTUM. The sites of application should be rotated, with an interval of 7 days between applications to the same site. The area selected should not be oily, damaged, or irritated.
  • The system should be applied immediately after opening the pouch and removing the protective release liner. The system should be pressed firmly in place, making sure there is good contact with the skin, especially around the edges.
  • The patient should avoid swimming, showering, or washing the administration site for a minimum of 3 hours after application.
  • Mild skin irritation may be ameliorated by treatment of the affected skin with over-the-counter topical hydrocortisone cream applied after system removal. Applying a small amount of 0.1% triamcinolone acetonide cream to the skin under the central drug reservoir of the testosterone system has been shown to reduce the incidence and severity of skin irritation.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Testosterone in adult patients.

Non–Guideline-Supported Use

Osteoporosis, Male

  • Dosing information
  • 5 to 10 mg/day[1]

Weight Gain

  • Dosing information
  • '150 and 300 mcg/day[2]

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Testosterone (transdermal) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Testosterone in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Testosterone in pediatric patients.

Contraindications

  • Testosterone is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate.
  • Testosterone is contraindicated in women who are, or who may become pregnant, or who are breastfeeding. Testosterone may cause fetal harm when administered to a pregnant woman. Testosterone may cause serious adverse reactions in nursing infants. If a pregnant woman is exposed to testosterone, she should be apprised of the potential hazard to the fetus.

Warnings

Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer

Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. Patients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating treatment. It is appropriate to re-evaluate patients 3 to 6 months after initiation of treatment, and then in accordance with prostate cancer screening practices.

Polycythemia

Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating testosterone treatment. It is appropriate to re-evaluate the hematocrit 3 to 6 months after starting testosterone treatment, and then monitor annually. Discontinue testosterone therapy if the hematocrit becomes elevated. Testosterone therapy may be restarted when the hematocrit decreases to an acceptable level. An increase in red blood cell mass may increase the risk of thromboembolic events.

Venous Thromboembolism

There have been post marketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products such as testosterone. Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic events is suspected, discontinue treatment with testosterone and initiate appropriate workup and management.

Use in Women and Children

Women and children should not use testosterone. Use in women and children has not been studied with testosterone. Due to lack of controlled studies in women and potential virilizing effects, testosterone is not indicated for use in women and children.

Potential for Adverse Effects on Spermatogenesis

At large doses of exogenous androgens, including testosterone, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) that could lead to adverse effects on semen parameters including reduction of sperm count.

Hepatic Adverse Effects

Prolonged use of high doses of orally active 17-alpha-alkyl androgens (methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. Testosterone is not known to cause these adverse effects.

Edema

Androgens, including testosterone, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease.

Gynecomastia

Gynecomastia may develop and persist in patients being treated with androgens, including testosterone, for hypogonadism.

Sleep Apnea

The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity and chronic lung disease.

Lipids

Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy.

Hypercalcemia

Androgens, including testosterone, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients.

Decreased Thyroxine-Binding Globulin

Androgens, including testosterone, may decrease concentrations of thyroxine-binding globulins, resulting in decreased total T4 serum concentration and increased resin uptake of T3 and T4. Free thyroid hormone concentration remains unchanged and there is no clinical evidence of thyroid dysfunction.

Magnetic Resonance Imaging MRI

Skin burns have been reported at the application site in patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because testosterone contains aluminum, it is recommended to remove the system before undergoing an MRI.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 shows the adverse reactions that were reported by > 3% of 36 hypogonadal men who were treated with testosterone 2 mg/day, 4 mg/day, or 6 mg/day for 28 days. Of note, all hypogonadal men studied had been stable users of topical testosterone replacement products prior to the study and there was no washout period between therapies. Furthermore, there was only one subject titrated to 6 mg/day and he withdrew from the study prematurely.

This image is provided by the National Library of Medicine.

Other less common adverse reactions reported by < 3% of patients included: application site erythema, application site exfoliation, chills, diarrhea, fatigue, gastroesophageal reflux disease, hemarthrosis, hematuria, headache, polyuria, and prostatitis. The overall incidence of application site reactions of any kind was 28% (10 subjects with 13 adverse reactions). No serious adverse reactions to testosterone 2 mg/day and 4 mg/day were reported during the clinical trial. Table 2 shows the adverse reactions that were reported in > 3% of 122 patients in clinical studies with testosterone dosage strengths of 2.5 mg/day, 5 mg/day, and 7.5 mg/day. The most common adverse reactions reported were application site reactions. Transient mild to moderate erythema was observed at the site of application in the majority of patients at some time during treatment. The overall incidence of application site reactions of any kind was 48% (59 subjects with 107 adverse reactions).

This image is provided by the National Library of Medicine.

The following reactions occurred in less than 3% of patients: rash, gastrointestinal bleeding, fatigue, body pain, pelvic pain, hypertension, peripheral vascular disease, increased appetite, accelerated growth, anxiety, confusion, decreased libido, paresthesia, thinking abnormalities, vertigo, acne, bullae at application site, mechanical irritation at application site, rash at application site, contamination of application site, prostate carcinoma, dysuria, hematuria, impotence, urinary incontinence, urinary tract infection, and testicular abnormalities.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of testosterone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Vascular Disorders:

Venous thromboembolism

Drug Interactions

Insulin

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirement.

Oral Anticoagulants

Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time is recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.

Corticosteroids

The concurrent use of testosterone with ACTH or corticosteroids may result in increased fluid retention and should be monitored, particularly in patients with cardiac, renal or hepatic disease.

Triamcinolone

The topical administration of 0.1% triamcinolone cream to the skin under the central drug reservoir prior to the application of the testosterone system did not significantly alter transdermal absorption of testosterone; however, the rate of complete adherence was lower. Pre treatment with triamcinolone ointment formulation significantly reduced testosterone absorption from the testosterone system.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): X Pregnancy Category X — Testosterone is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a female fetus to androgens may result in varying degrees of virilization. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Testosterone (transdermal) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Testosterone (transdermal) during labor and delivery.

Nursing Mothers

Although it is not known how much testosterone transfers into human milk, Testosterone is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Testosterone and other androgens may adversely affect lactation.

Pediatric Use

Safety and efficacy of testosterone have not been established in males <18 years of age. Improper use may result in acceleration of bone age and premature closure of epiphyses.

Geriatic Use

There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing testosterone to determine whether efficacy in those over 65 years of age differs from younger patients. Additionally, there are insufficient long-term safety data in geriatric patients utilizing testosterone to assess a potential incremental risk of cardiovascular disease and prostate cancer.

Gender

There is no FDA guidance on the use of Testosterone (transdermal) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Testosterone (transdermal) with respect to specific racial populations.

Renal Impairment

No studies were conducted in patients with renal impairment.

Hepatic Impairment

No studies were conducted in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Testosterone (transdermal) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Testosterone (transdermal) in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Testosterone (transdermal) Administration in the drug label.

Monitoring

There is limited information regarding Testosterone (transdermal) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Testosterone (transdermal) and IV administrations.

Overdosage

No cases of overdose with testosterone have been reported in clinical trials. There is one report of acute overdosage by injection of testosterone enanthate: testosterone concentrations of up to 11,400 ng/dL were implicated in a cerebrovascular accident. Treatment of overdosage would consist of discontinuation of testosterone together with appropriate symptomatic and supportive care.

Controlled Substance

Testosterone contains testosterone, a Schedule III controlled substance under the Anabolic Steroids Control Act.

Abuse

Anabolic steroids, such as testosterone, are abused. Abuse is often associated with adverse physical and psychological effects.

Dependence

Although drug dependence is not documented in individuals using therapeutic doses of anabolic steroids for approved indications, dependence is observed in some individuals abusing high doses of anabolic steroids. In general, anabolic steroid dependence is characterized by any three of the following:

  • Taking more drug than intended
  • Continued drug use despite medical and social problems
  • Significant time spent in obtaining adequate amounts of drug
  • Desire for anabolic steroids when supplies of the drug are interrupted
  • Difficulty in discontinuing use of the drug despite desires and attempts to do so
  • Experience of withdrawal syndrome upon discontinuation of anabolic steroid use

Pharmacology

Template:Px
Template:Px
Testosterone (transdermal)
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
Identifiers
CAS number 58-22-0

57-85-2 (propionate ester)
ATC code G03BA03
PubChem 6013
DrugBank DB00624
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 288.42
SMILES eMolecules & PubChem
Physical data
Melt. point 155 °C (311 °F)
Spec. rot +110.2°
SEC Combust −11080 kJ/mol
Pharmacokinetic data
Bioavailability Low (due to extensive first pass metabolism)
Metabolism Liver, testis and prostate
Half life 2–4 hours
Excretion Urine (90%), feces (6%)
Therapeutic considerations
Licence data

US

Pregnancy cat.

X(US) Contraindicated due to teratogenic effects

Legal status

Schedule IV(CA) Schedule III(US) Template:Unicode Prescription only

Routes Intramuscular injection, transdermal (cream, gel, or patch), sub-'Q' pellet

Mechanism of Action

Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement; vocal cord thickening; and alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Signs/symptoms associated with male hypogonadism include erectile dysfunction and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics, and osteoporosis. Male hypogonadism has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter Syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

Structure

Testosterone (testosterone transdermal system) is designed to deliver testosterone continuously for 24 hours following application to intact, non-scrotal skin (e.g., back, abdomen, thighs, upper arms). Two strengths of testosterone are available that deliver approximately 2 mg or 4 mg of testosterone per day. Testosterone has a central drug delivery reservoir surrounded by a peripheral adhesive area. The testosterone 2 mg/day system has a total contact surface area of 32 cm2 with a 6.0 cm2 central drug delivery reservoir containing 9.7 mg testosterone USP, dissolved in an alcohol-based gel. The testosterone 4 mg/day system has a total contact surface area of 39 cm2 with a 12.0 cm2 central drug delivery reservoir containing 19.5 mg testosterone USP, dissolved in an alcohol-based gel. Testosterone USP is a white, or creamy white crystalline powder or crystals chemically described as 17ß-hydroxyandrost-4-en-3-one.

This image is provided by the National Library of Medicine.

The testosterone systems have six components as shown in Figure 1. Proceeding from the top toward the surface attached to the skin, the system is composed of (1) metallized polyester/Surlyn® (ethylene-methacrylic acid copolymer)/ethylene vinyl acetate backing film with alcohol resistant ink, (2) a drug reservoir of testosterone USP, alcohol USP, glycerin USP, glycerol monooleate, methyl laurate, sodium hydroxide NF, to adjust pH, and purified water USP, gelled with carbomer copolymer Type B NF, (3) a permeable polyethylene microporous membrane, and (4) a peripheral layer of acrylic adhesive surrounding the central, active drug delivery area of the system. Prior to opening of the system and application to the skin, the central delivery surface of the system is sealed with a peelable laminate disc (5) composed of a five-layer laminate containing polyester/polyesterurethane adhesive/aluminum foil/polyester-urethane adhesive/polyethylene. The disc is attached to and removed with the release liner (6), a silicone-coated polyester film, which is removed before the system can be used.

This image is provided by the National Library of Medicine.

The active ingredient in the system is testosterone. The remaining components of the system are pharmacologically inactive.

Pharmacodynamics

No specific pharmacodynamic studies were conducted using testosterone.

Pharmacokinetics

Absorption

Testosterone delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate the normal concentration range (300 - 1030 ng/dL) seen in healthy men. Testosterone provides a continuous daily dose of testosterone in a self-contained transdermal system. Following testosterone application, testosterone is continuously absorbed during the 24-hour dosing period with a median (range) Tmax of 8 (4-12) hours.

Distribution

Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.

Metabolism

Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and dihydrotestosterone (DHT). During steady-state pharmacokinetic studies in hypogonadal men treated with testosterone, the average DHT:T and E2:T ratios were approximately 1:10 and 1:200, respectively.

Excretion

There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Upon removal of the testosterone systems, serum testosterone concentrations decrease with an apparent half-life of approximately 70 minutes. Hypogonadal concentrations are reached within 24 hours following system removal. There is no accumulation of testosterone during continuous treatment.

Effect of Showering

In a two-way crossover study, the effects of showering on the pharmacokinetics of total testosterone following a single application of testosterone 4 mg/day were assessed in 16 hypogonadal males. Showering 3 hours after application of testosterone increased Cavg by 0.5% and decreased Cmax by 0.4% respectively, as compared to not showering. The systemic exposure to testosterone was similar following applications with or without showering 3 hours after application.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. Testosterone was negative in the in vitro Ames and in the in vivo mouse micro nucleus assays. The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

Clinical Studies

Testosterone 2 mg/day and 4 mg/day were studied in a trial designed to evaluate the use and titration of 2 mg/day and 4 mg/day systems in a clinic setting of 40 men with hypogonadism. Thirty-eight of the 40 subjects (95%) who were enrolled into the study were white and 2 subjects were African American. Ten (25%) subjects were hispanic and 30 (75%) were non-hispanic. Men were between 34 and 76 years of age (mean: 55 years). Patients had previously been on stable therapy of testosterone 5 mg; Androgel® 2.5 g, 5 g, 7.5 g or 10 g; or Testim® 2.5 g or 5 g daily before switching to testosterone 4 mg/day. Patients applied an testosterone 4 mg/day system around 10 p.m. once daily for 14 days, and then were titrated up to 6 mg/day or down to 2 mg/day according to a morning serum testosterone concentration obtained at 6 a.m. on Day 8. Out of 36 patients who entered the study, 31 (86%) patients remained on the 4 mg/day dose, 4 (11%) were titrated downward to 2 mg/day, and 1 (3%) was titrated upward to 6 mg/day based on the Day 8 testosterone concentrations. The one patient that was titrated to 6 mg/day discontinued from the study for a non-safety related reason. Of the patients who were receiving testosterone 5 mg/day prior to study entry (n = 11), 10 remained at 4 mg/day after titration, and 1 was titrated down to the 2 mg/day dose. After a total of 28 days of therapy, 34 of the 35 subjects (97%) had serum testosterone Cavg within the normal range during the dosing period, with the lower bound of the 95% confidence interval for this estimate being 85% (Table 3). One subject who received testosterone 4 mg/day treatment had serum testosterone Cavg below 300 ng/dL and none had Cavg concentrations above 1030 ng/dL. The mean (SD) serum testosterone Cmax following treatment with the 2 mg/day (N = 4) and 4 mg/day (N = 31) systems was 648 (145) ng/dL and 696 (158) ng/dL, respectively. Table 3 summarizes testosterone Cavg categories by treatment.

This image is provided by the National Library of Medicine.

Figure 2 summarizes the pharmacokinetic profiles of total testosterone in 35 patients completing 28 days of testosterone treatment applied as a starting dose of 4 mg/day for the initial 14 days followed by a possible dose titration.

This image is provided by the National Library of Medicine.

In separate clinical studies using the testosterone 2.5 mg/day system, 1% used 2.5 mg daily, 93% of patients used 5 mg daily, and 6% used 7.5 mg daily. The hormonal effects of testosterone 2.5 mg/day system as a treatment for male hypogonadism was demonstrated in four open-label trials that included 94 hypogonadal men, ages 15 to 65 years. In these trials, testosterone produced average morning serum testosterone concentrations within the normal reference range in 92% of patients.

How Supplied

Testosterone (testosterone transdermal system) 2 mg/day. Each system contains 9.7 mg testosterone USP for delivery of 2 mg of testosterone per day. Cartons of 60 systems NDC 52544-076-60 Testosterone (testosterone transdermal system) 4 mg/day. Each system contains 19.5 mg testosterone USP for delivery of 4 mg of testosterone per day. Cartons of 30 systems NDC 52544-077-30

Storage

Store at 20-25°C (68-77°F). [See USP controlled room temperature.] Apply to skin immediately upon removal from the protective pouch. Do not store outside the pouch provided. Damaged systems should not be used. The drug reservoir may be burst by excessive pressure or heat. Discard systems in household trash in a manner that prevents accidental application or ingestion by children, pets or others.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

This image is provided by the National Library of Medicine.

Precautions with Alcohol

Alcohol-Testosterone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Androderm
  • Androgel
  • Striant
  • Testim
  • Testro AQ
  • Testopel Pellets
  • Axiron
  • Fortesta

Look-Alike Drug Names

Testoderm - Testoderm TTS Testoderm - Testoderm with Adhesive Testoderm with Adhesive - Testoderm TTS[3]

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G; et al. (2001). "Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men". Clin Endocrinol (Oxf). 54 (6): 739–50. PMID 11422108.
  2. ↑ Miller K, Corcoran C, Armstrong C, Caramelli K, Anderson E, Cotton D; et al. (1998). "Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study". J Clin Endocrinol Metab. 83 (8): 2717–25. doi:10.1210/jcem.83.8.5051. PMID '9709937 Check |pmid= value (help).
  3. ↑ "https://www.ismp.org". External link in |title= (help)

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