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Androgen is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of masculine characteristics in vertebrates by binding to androgen receptors. This includes the activity of the accessory male sex organs and development of male secondary sex characteristics. Androgens, which were first discovered in 1936, are also called androgenic hormones or testoids. Androgens are also the original anabolic steroids. They are also the precursor of all estrogens, the female sex hormones. The primary and most well-known androgen is testosterone.

Psychological correlatesEdit

Influences of androgens on childhood gender non-conformityEdit

Fetuses are exposed to prenatal androgens as early as 8 weeks into development. Male fetuses are exposed to much higher levels of androgens than female fetuses. It’s been found that toy preferences, play-mates, and play-styles vary with the child’s exposure to androgens. Regardless of the biological sex of the child, increased androgen exposure is associated with more masculine-type behaviours, while decreased androgen exposure is associated with more feminine-type behaviours.

Types of androgensEdit

A subset of androgens, adrenal androgens, includes any of the 19-carbon steroids synthesized by the adrenal cortex, the outer portion of the adrenal gland, that function as weak steroids or steroid precursors, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione.

Besides testosterone, other androgens include:

  • Dehydroepiandrosterone (DHEA): a steroid hormone produced from cholesterol in the adrenal cortex, which is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.
  • Androstenedione (Andro): an androgenic steroid, which is produced by the testes, adrenal cortex, and ovaries. While androstenediones are converted metabolically to testosterone and other androgens, they are also the parent structure of estrone. Use of androstenedione as an athletic or body building supplement has been banned by the International Olympic Committee as well as other sporting organizations.
  • Androsterone: a chemical by-product created during the breakdown of androgens, or derived from progesterone, that also exerts minor masculinising effects, but with one-seventh the intensity of testosterone. It is found in approximately equal amounts in the plasma and urine of both males and females.
  • Dihydrotestosterone (DHT): a metabolite of testosterone that is actually a more potent androgen in that it binds more strongly to androgen receptors.

Androgen functionsEdit

Development of the male Edit

Testes formationEdit

During mammalian development, the gonads are at first capable of becoming either ovaries or testes.[1] In humans, starting at about week 4, the gonadal rudiments are present within the intermediate mesoderm adjacent to the developing kidneys. At about week 6, epithelial sex cords develop within the forming testes and incorporate the germ cells as they migrate into the gonads. In males, certain Y chromosome genes, particularly SRY, control development of the male phenotype, including conversion of the early bipotential gonad into testes. In males, the sex cords fully invade the developing gonads.

Androgen productionEdit

The mesoderm-derived epithelial cells of the sex cords in developing testes become the Sertoli cells, which will function to support sperm cell formation. A minor population of nonepithelial cells appear between the tubules by week 8 of human fetal development. These are Leydig cells. Soon after they differentiate, Leydig cells begin to produce androgens.

Androgen effectsEdit

The androgens function as paracrine hormones required by the Sertoli cells to support sperm production. They are also required for masculinization of the developing male fetus (including penis and scrotum formation). Under the influence of androgens, remnants of the mesonephron, the Wolffian ducts, develop into the epididymis, vas deferens and seminal vesicles. This action of androgens is supported by a hormone from Sertoli cells, Müllerian inhibitory hormone (MIH), which prevents the embryonic Müllerian ducts from developing into fallopian tubes and other female reproductive tract tissues in male embryos. MIH and androgens cooperate to allow for the normal movement of testes into the scrotum.

Early regulationEdit

Before the production of the pituitary hormone luteinizing hormone (LH) by the embryo starting at about weeks 11–12, human chorionic gonadotrophin (hCG) promotes the differentiation of Leydig cells and their production of androgens at week 8. Androgen action in target tissues often involves conversion of testosterone to 5α-dihydrotestosterone (DHT).


During puberty, androgen, LH and FSH production increase and the sex cords hollow out, forming the seminiferous tubules, and the germ cells start to differentiate into sperm. Throughout adulthood, androgens and FSH cooperatively act on Sertoli cells in the testes to support sperm production[1]. Exogenous androgen supplements can be used as a male contraceptive. Elevated androgen levels caused by use of androgen supplements can inhibit production of LH and block production of endogenous androgens by Leydig cells. Without the locally high levels of androgens in testes due to androgen production by Leydig cells, the seminiferous tubules can degenerate resulting in infertility.

Inhibition of fat depositionEdit

Males typically have less body fat than females. Recent results indicate androgens inhibit the ability of some fat cells to store lipids by blocking a signal transduction pathway that normally supports adipocyte function.[2] Also, androgens, but not estrogens, increase beta adrenergic receptors while decreasing alpha adrenergic receptors- which results in increased levels of epinephrine/ norepinephrine due to lack of alpha-2 receptor negative feedback and decreased fat accumulation due to epinephrine/ norepinephrine then acting on lipolysis-inducing beta receptors..

Muscle massEdit

Males typically have more skeletal muscle mass than females. Androgens promote the enlargement of skeletal muscle cells and probably act in a coordinated manner to enhance muscle function by acting on several cell types in skeletal muscle tissue[2].


Circulating levels of androgens can influence human behavior because some neurons are sensitive to steroid hormones. Androgen levels have been implicated in the regulation of human aggression[2] and libido. Indeed, androgens are capable of altering the structure of the brain in several species, including mice, rats, and primates, producing sex differences.[3] Numerous reports have shown androgens alone are capable of altering the structure of the brain,[4] but identification of which alterations in neuroanatomy stem from androgens or estrogens is difficult, because of their potential for conversion.

Screening Methods for AndrogensEdit

  • The whole animal (in vivo),
  • A combination of the whole animal and isolated organ(s) (ex vivo),
  • Isolated and cultured whole or sections/minced organs, i.e., testis (in vitro),
  • Isolated and cultured cells from the testis (in vitro), and
  • Cell lines (in vitro).

Whole Animal Methods (In Vivo) Intact animals used to measure androgenic activity (Allen and Doisy, 1924; Hershberger et al., 1953). In vivo methods - Take advantage of animal’s innate hormone-directed tissue development and maintenance responses and - Use these responses to identify whether administered substances alter the normal response. Animal’s inherent capacity to produce these hormones must be removed.

  1. Castration.
  2. Immature or juvenile animals used

(M. Chaturvedia, P.C. Mali, A.S. Ansarib; Pharmacology: 2003; 68:38-48)

For androgenicity evaluation of test subs. rats were divided into four groups:
Group I- animals were castrated 30 days before the experiment to serve as controls
Group II, III and IV subjected to castration 30 days before the experiments, followed by administration of test subs., testosterone
propionate (0.01 mg/rat/alternate day s.c.), and test subs. with testosterone propionate, respectively, for 30 days.
Studied-- 	cauda epididymis sperm motility and density,
	Number of pups,
		The weights of testes, epididymis, seminal vesicle, and prostate 

Histoarchitecture of the testesEdit

Endocrine challenge test (ECT). (Anderson et al., 1992).

Bioassay - to evaluate gonadal response to a substance by measuring the steroid hormone production and release following administration of test subs. The intact mature animal is challenged with GnRH or an LH- or FSH-like substance that stimulates a hormonal response. Serial blood samples collected and measured to evaluate whether the substance being tested causes increased testosterone Techniques used include tail vein sampling, tail vein treatments and/or jugular catheterization (Fail et al., 1995; Fail and Anderson, 2002). A number of different endpoints have been used.

  • Plasma testosterone, before (basal) and after stimulation. Testosterone concentrations measured by RIA (Fail et al., 1995; 1996).
  • Epididymis weight, caudal sperm count, testicular sperm heads, and sperm motility (Fail et al., 1995; 1996).

Combination of Whole Animal and Isolated Organs Method (ex vivo)Edit

  • First involves treating immature or adult animals according to selected dosing regimen.
  • Route, duration of exposure are not constrained.
  • In addition to the acute exposures, exposures for ex vivo studies can actually begin as early as gestation and continue for as long as the life expectancy of animal being tested.
  • During the in-life exposure period, blood samples can be collected at specified times for serum hormone analysis.
  • After the exposure period is completed, animal is killed, at which time final necropsy

specimens collected, and the testis isolated.

  • The gonads are then processed according to the type of in vitro preparation that was selected to assess the test substance’s effect.

Isolated Organ Methods (in vitro)Edit

*The organs where steroidogenesis occurs removed from animal & kept viable, thereby providing an isolated organ method for assessing
substances as stimulants of the steroidogenic pathway. 
  • Organs, once isolated, can be used whole or further processed into sections or minced organ preparations
  • These preparations allow effect of given test substance to be measured without influence of other organs or systems/other physiological factors.
  • The integrity and interrelationship of the cells and tissues within the organ remain intact.
  • These preparations retain the cellular and biochemical pathways that involve the receptor and second messenger.
  1. way in which the organ is processed.
  • Whole organ-- after the organ is removed and placed in media, no further processing occurs
  • Sectioned organ --For the testes, an organ section refers to an organ that has been cut such that each section constitutes 1/8 to ½ the size of the whole organ, i.e., 50 to 250 mg (rat testis). *Minced organ -- organ that has been cut into very small sizes, i.e., 1 to 50 mg (rat testis).

The perfused testisEdit

  1. Provides a method to simulate biosynthesis and secretion of testicular steroid hormones

Developed for the rabbit by Vandemark and Ewing (1963), modified for the rat by Chubb and Ewing (1979).

  1. Apparatus is sterilized and then assembled.
  2. The system must be air-free to prevent bubbles from entering the perfusate and blocking flow.
  3. Testis is removed, spermatic artery cannulated, organ flushed of blood with perfusate solution.
  4. The testis is placed in the organ chamber and perfusion initiated.
  5. Test substance given after a preliminary perfusion for approximately 1 hour, the temperature (370 C), rate of flow (20 mL/hr), and pH (7.4) are monitored and maintained.
  6. The perfusion can be maintained for 6 to 10 hours.
  7. Samples are collected from the perfusate for analysis.

Simple Whole Organ Incubation techniqueEdit

  • Involves removal of the testis and incubation of the organ in medium for testing.
  • For the whole testis (Deb et al., 1980), animal anesthetized or euthanized & testes removed.
  • The testes are incubated in Kreb-Ringer-bicarbonate solution (pH 7.6) at 370 C & atmosphere of 95 percent O2 and 5 percent CO2
  • Testes are incubated with or without the substance being tested, as well as with or without stimulant, e.g., LH.

Screening for AR activity using Gene expression assaysEdit

  • Assay involves transient transfection of a tester cell line with a plasmid base receptor and the reporter, followed by chemical exposure and measurement of the modulation of gene expression.

· KB2 assay (Vickie S. Wilson; 2002: Toxicological Sciences 66, 69-81) · Describe the effects of androgens in a stably transformed cell line that they developed (MDA-KB2), which expresses the human AR (hAR) and an AR-responsive promoter linked to a luciferase reporter gene (MMTV-luc). · Main advantage of KB2 assay -- it employs a genetically modified cell line, which eliminates the effort and inherent variability associated with repeated transient transfections. · The breast cancer cell line, MDA-MB-453, was stably transformed with the MMTV.luciferase.neo reporter gene construct. · Since both GR and AR are present in the MDA-MB-453 cells, and both receptors can act through the MMTV promoter, compounds that act through either AR or GR activate the MMTV luciferase reporter. · AR agonists such as dihydrotestosterone (DHT), and GR agonists such as dexamethasone (DEX), corticosterone, and aldosterone induce luciferase expression at appropriate concentrations.

· DHT consistently produced 3–9-fold induction at concentrations from 0.1 to 10 nM. · To distinguish AR- from GR-mediated ligands, chemicals were assayed concurrently with the antiandrogen, hydroxyflutamide (OHF), which blocks AR- but not GR-mediated responses. · These cells are relatively easy to culture and maintain. · Responsiveness was monitored over time and was stable for more than 80 passages. · Some advantages -- relatively rapid (2 days), eliminates the need for transfection, can be conducted in a 96-well plate format, produces consistent reproducible results

  • Construction and verification of reporter plasmid containing MMTV. neo.luc-- The neomycin gene was removed from pcDneo and inserted into pMMTV.luc
  • Transformation, isolation, and screening of stable clones.

MDA-MB-453 cells (ATCC No. HTB 131) used for transformation. Cells were seeded at 2 x 105 cells per 60-mm culture dish in maintenance medium, then transformed using Fugene 6 (Roche) per manufacturer's protocol, with 5 µg pMMTV.luc.neo per dish. To screen clones for responsiveness to an androgen agonist, cells grown from individual colonies were plated at 1 x 104 cells per well in 96-well luminometer plates, allowed to attach. When cells were attached, the medium was replaced with freshly prepared dosing medium containing ethanol only (negative control), an agonist (dihydrotestosterone, DHT; 1 nM), or the agonist plus a known competitor (hydroxyflutamide, OHF; 1 M). Cells were dosed with 100 µl of medium/well and incubated for 20–24 h, --harvested with 25 µl/well of lysis buffer and assayed for luciferase reporter activity.

Relative light units per well determined using a 96-well MLX Luminometer.
Clones with a minimum 2-fold response to 1 nM DHT were retained in culture.
The final clone (MDA-kb2) was chosen based on appropriate ligand responsiveness and genetic stability over time.
  • Maintenance of cultures and transcriptional activation assays.
-MDA-kb2 cells stably transformed with the pMMTV.neo.luc reporter gene construct were maintained in L-15 media supplemented with, 100
U/ml penicillin, 100 µg/ml streptomycin, and 0.25 µg/ml amphotericin B at 37°C, without CO2.
-For experiments, cells were plated at 1 x 104 cells per well in 100 µl of medium in 96-well luminometer plates.

-When cells were attached (4–6 h), medium was removed and replaced with dosing medium. Stock solutions for each chemical were prepared at 1000x in ethanol. - Dosing medium was prepared at the time of treatment by aliquoting 1 µl of stock solution into 1 ml of maintenance medium -Vehicle control wells contained 100 µl medium/ well with1 µl of ethanol/ml of medium. Each plate also contained either 0.1 or 1.0 nM DHT, or DHT/plus 1 µM OHF as agonist control. -Cells were incubated overnight at 37°C without CO2.

Luciferase activity was assayed --using an MLX microtiter plate luminometer and quantified as relative light units (RLU).

-Relative light units were converted to fold induction above the vehicle control value for each replicate for statistical analysis. -Stability of Androgenic Response and Baseline Activity Androgen-induced luciferase activity measured over approximately 9 months of continuous culture to assess the stability and responsiveness of the MDA-kb2 clone.

-cells were assayed over more than 80 passages for their response to 1 nM DHT.

-At early passages, luciferase induction relative to solvent controls was about 10 fold.

-In continuous culture, luciferase induction dropped over time, but responsiveness stabilized at 30 to 40 passages.

-In later passages, a minimum of 5–6-fold induction in response to 1 nM DHT was consistently maintained over the remaining test period for more than 80 passages, demonstrating stable expression of the luciferase gene. P. C. Hartig,1, Toxicological Sciences 66, 82-90 (2002)

  • Attempt to deliver the genes via replication-defective adenovirus transduction
  • describe the responses of several androgens in two AR-responsive in vitro assays. These assays used transduced MDA-453 and CV-1 cells, cell lines.
  • Ad/mLuc7 virus used, which contains the luciferase gene regulated by the glucocorticoid-inducible hormone response element found in the mouse mammary tumor virus (MTV) LTR
  • Transduction assays were performed in 96-well plates.

· Twenty-four h prior to transduction, 5 x 104 cells were plated per well. · Medium was removed and replaced with 20 µl of control medium or medium with diluted virus. · MDA cells (which contain endogenous AR) were transduced with Ad/mLuc7 reporter virus at a multiplicity of infection (MOI) of 50 (i.e., 50 virions per cell). · CV-1 cells (which lack native AR) were transduced with Ad/mLuc7 at a MOI of 50 and Ad5hAR at a MOI of one. · Dishes were rocked every 15 min for 1 h, incubated 3 additional h, · 200 µl medium/medium + test chemicals added to each well · followed by a 48-h incubation. · Plates were either frozen at –80°C, or assayed immediately for luciferase activity. · Luciferase activity was quantitated in an MLX microtiter plate luminometer, data expressed in relative light units (RLU). · For androgen agonists, which stimulate luciferase expression, treatments compared to the media/ethanol control group · Relative light units were converted to fold induction above the media value for each replicate

(L. G. Parks; Toxicological Sciences 62, 257-267 (2001)

COS whole cell human androgen receptor (hAR) binding assayEdit

  • In 3 blocks, COS cells (SV-40 transformed monkey kidney line ATCC # CRL-1650) were transiently transfected with hAR expression vector pCMVhAR
  • COS cells were plated at 200,000 cells/well in 12 plates and transfected with 1 µg of pCMVhAR
  • After a 3-h transfection period, cells were washed and incubated overnight
  • Twenty-four hours later, medium replaced with 200 µl of serum-free/phenol red-free DMEM with R1881 plus 200 microliters of medium containing tast substance (400-µl incubation volume, with a concentration factor of 40x).
  • Cells were incubated for 2 h with 5 nM [3H] R1881 at 37°C under an atmosphere of 5% CO2.
  • Cells were washed in phosphate-buffered saline and lysed in 200 µl ZAP

(0.13 M ethylhexadecyldimethylammonium bromide with 3% glacial acetic acid).

  • The lysate was added to 5 ml OPTI-fluor scintillation cocktail and radioactivity was counted using a Beckman LS 5000 TD counter

· 1 µM hydroxyflutamide was added to half of the samples to see if this potent antiandrogen would block the test substance-induced luciferase activity. · Cells also were exposed to 1 nM DHT as a positive control.

CV-1 AR and GR 40-dependent transcriptional activation assays

  • Experiments, each with several replicates, were conducted to determine induced AR- or GR-dependent gene expression in CV-1 cells (monkey kidney line, ATCC # CCL-70).
  • 200,000 CV-1 cells were plated in a 60-mm dish and then transiently cotransfected with 1 µg pCMVhAR and 5 µg MMTV-luciferase reporter using 5 µl Fugene reagent in 95 µl serum-free medium as per the manufacturer's protocol.

· Twenty-four h after transfection, medium was aspirated and replaced with 2 ml of medium containing test substance. · Cells then incubated at 37°C under 5% carbon dioxide. · After 5 h of exposure, medium was removed, and cells were washed once with phosphate-buffered saline and harvested with 500 µl lysis buffer. · Relative light units of 0.05-ml aliquots of lysate determined using a Monolight 2010 luminometer.

COS cell immunocytochemistry Experiment conducted to visualize, by immunofluorescence, the ligand-induced nuclear translocation of hAR in COS cells.

·Two chamber slides were seeded with 100,000 cells/chamber in 2 ml DMEM supplemented with 10% FBS ·Cells transfected with 0.5 µg pCMVhAR ·Following transfection, 2 ml medium containing test substance, added to slides, incubated for 24 h at 37°C under 5% CO2. ·The next day, medium removed, cells washed once with DPBS (Dulbecco's phosphate buffered saline), allowed to dry for 45 min at room temperature, fixed for 10 min with 95% ethanol (-20°C), blocked with 5% BSA, and incubated overnight with primary AR antibody (1:1000) at 4°C. ·The following day, cells were washed once with DPBS and incubated with fluorescently labeled secondary antibody for 30 min at room temperature. ·To visualize the nuclei, cells were counter-stained with DAPI, a DNA stain, mounted with fluoromount slides examined using Microscope at 200 x magnification. ·The localization of the AR was classified as either perinuclear or nuclear in a blinded fashion from 10 randomly selected fields from a slide for each site. ·In another experiment, cells were exposed to 1 nM DHT, as a positive control.

Novel yeast bioassay system for detection of androgenic compounds. Lee HJ, Lee YS, Kwon HB, Lee K.;Toxicol In Vitro. :2003 Apr;17(2):237-44.

Report the development of a rapid, simple, effective yeast detection system for androgenic compounds, based on the yeast two-hybrid protein interaction.

  • A yeast strain, ARhLBD-ASC1, was established by co-transformation of yeast cells harboring a lacZ reporter plasmid with two vectors expressing each of LexA fused hinge-ligand binding domain (hLBD) of androgen receptor (AR) and B42 fused ASC-1 that interacts with
AR-hLBD in an androgen-dependent manner.
  • In this strain, androgens, but not other hormones, strongly stimulated the beta-galactosidase activity in a dose-dependent manner.

Insensitivity to androgen in humansEdit

Reduced ability of a XY karyotype fetus to respond to androgens can result in one of several problems, including infertility and several forms of intersex conditions. See androgen insensitivity syndrome (AIS).


  1. ^  Online textbook: "Developmental Biology" 6th ed. By Scott F. Gilbert (2000) published by Sinauer Associates, Inc. of Sunderland (MA).
  2. ^  Online textbook: "Endocrinology: An Integrated Approach" by S. S. Nussey and S. A. Whitehead (2001) published by BIOS Scientific Publishers, Ltd; Oxford, UK.
  3. ^  Full text article available in PDF format: "Testosterone Inhibits Adipogenic Differentiation in 3T3-L1 Cells: Nuclear Translocation of Androgen Receptor Complex with {beta}-Catenin and TCF4 may Bypass Canonical Wnt Signaling to Downregulate Adipogenic Transcription Factors" by R. Singh, J. N. Artaza, W. E. Taylor, M. Braga, X. Yuan, N. F. Gonzalez-Cadavid and S Bhasin in Endocrinology (2005) Entrez PubMed 16210377
  4. ^  Androgen Receptor in Human Skeletal Muscle and Cultured Muscle Satellite Cells: Up-Regulation by Androgen Treatment by Indrani Sinha-Hikim, Wayne E. Taylor, Nestor F. Gonzalez-Cadavid, Wei Zheng and Shalender Bhasin in The Journal of Clinical Endocrinology & Metabolism (2004 ) volume 89 pages 5245-5255.
  5. ^  Full text article available in PDF format: "Testosterone and aggressiveness" by Marco Giammanco, Garden Tabacchi, Santo Giammanco, Danila Di Majo and Maurizio La Guardia in Endocrinology (2005) Entrez PubMed 16210377

See alsoEdit


  1. Scott F. Gilbert; with a chapter on plant development by Susan R. Singer (2000). Scott F. Gilbert Developmental Biology, 6th, Sunderland, Massachusetts: Sinauer Associates.Template:Page needed
  2. 2.0 2.1 Singh R, Artaza JN, Taylor WE, et al. (January 2006). Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Endocrinology 147 (1): 141–54.
  3. Cooke B, Hegstrom CD, Villeneuve LS, Breedlove SM (October 1998). Sexual differentiation of the vertebrate brain: principles and mechanisms. Frontiers in Neuroendocrinology 19 (4): 323–62.
  4. Zuloaga DG, Puts DA, Jordan CL, Breedlove SM (May 2008). The role of androgen receptors in the masculinization of brain and behavior: what we've learned from the testicular feminization mutation. Hormones and Behavior 53 (5): 613–26.

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