Anti-androgens

An anti-androgen is a hormone receptor antagonist. A receptor antagonist is a compound that prevents or inhibits the effects of a hormone by binding to that particular hormones receptor, at which point no response is elicited. Anti-androgens bind to the receptor for the male sex hormone androgen, and prevent the normal biological responses of the tissues in the body.
         Since the early 1990s, significant attention has been focused on the potential for chemicals found in the environment to alter endocrine systems in animals including humans. This field of endocrine disrupters has quickly grown and now encompasses diverse areas of research such as immunology, toxicology, reproductive physiology, behavior, and ecology. Endocrine-active chemicals arise from many different sources, including pesticides, industrial chemicals, pharmaceuticals, and phytochemicals (Gray 2001).

Examples

Mechanism of Action

Anti-androgens use the hormone mechanism that works by blocking the appropriate receptors, competing for binding sites on the cell's surface, obstructing the androgens' pathway. This inhibits the ability for testosterone to bind and in turn a reduction in testosterone.

testosterone mechanism

anti-androgen mechanism

Reproductive Side Effects

Male fetuses exposed to anti-androgens during prenatal life are permanently demasculinized in their morphology and physiology (Hotchkiss 2002). Investigation of the effects of anti-androgens in developmental studies of male rats is consistent with androgen receptor antagonism. These effects include reduced anogenital distance (AGD), retention of nipples, genital malformations including cleft phallus and hypospadias, and sex accessory glands that were either reduced in mass or absent(Gray 1994; Wolf 2000). Furthermore, the critical window for inducing these changes appears to be around the period for reproductive differentiation (Wolf 2000).

         Differentiation of the male reproductive phenotype depends on both Mullerian-inhibiting substance (MIS) and testosterone. Lack of expression of these two hormones results in the development of the female phenotype (Jost 1953) whereas MIS is critical for the inhibition of the Mullerian ducts. Testosterone is important for differentiation of the Wolffian ducts, associated sex accessory tissues, and testicular descent (Jost 1970). Testosterone, reduced by the enzyme 5αreductase to dihydrotestosterone, is important for development of external genitalia and the prostate (Wilson and Lasnitzki 1971). Inappropriate expression or suppression of either MIS or testosterone results in abnormalities of the adult reproductive phenotype. Behaviorally, hormones act prenatally to organize neural systems that later can be activated by the same steroid hormones and elicit behavior such as hypersexuality and sexual deviation (Phoenix 1959).

Example: Testicular Feminization

Articles

Article Title: Antiandrogen exposure in utero disrupts expression of desert hedgehog and insulin-like factor 3 in the developing fetal rat testis
Summary: Testicular development is an androgend-dependent process, and fetal exposure to anti-androgens disrupt male sexual differentiation. A variety of testicular disorders may result from impared development of fetal Leydig and Sertoli cells. These scientists tested the hypothesis that exposure to anti-androgens during fetal development would interfere with testicular signaling which would impair Leydig cell differentiation within the desert hedgehog. Pregnant hedgehogs were exposed to the anti-androgen flutamide post conception and fetal testes were isolated at different points during gestation. Gene secretion of testosterone was measured and it was found that gene expression levels were significantly lower that the control (see chart below). They concluded that exposure to the anti-androgen flutamide interferes with Dhh signaling resulting in an impaired differentiation of the fetal Leydig cells and subsequently leading to abnormal testicular development and sexual differentiation. (Brokken)

chart

Article Title: Effects of maternal exposure to di-isononylphthalate (DINP) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) on steroidogenesis in the fetal rat testis and adrenal gland
Summary: This article investigated the effects of exposure of anti-androgens and its demascularizing affects. They found that exposure during the critical developmental window when sexual differentiation is happening caused clear abnormalities in the ultrastructure of steroidogenic cells in rat testis and adrenal gland. These structural alterations can disturb the development and function of the fetal testis and adrenal that may become evident later in life.  (Adammsson)

Conclusion

Discovery of new kinds of anti-androgens and reports of anti-androgen chemicals in the environment has gained interest in describing the role of anti-androgens in reproductive and behavioral development. Studies have shown (Adamsson 2009; Brokken 2009) that anti-androgens have had emasculating effects toward the exposed individuals and in turn have lowered reproductive viability. Through this knowledge the release of anti-androgens into the environment should be carefully monitored so the biodiversity of species and species reproduction is less affected. 

Sources

Adamsson, A. "Effects of maternal exposure to di-isononylphthalate (DINP) and 1,1 dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) on steroidogenesis in the fetal rat testis and adrenal gland." Reproduction Toxicology 1 (2009): 66-74. Print.

Brokken, L. J. "Antiandrogen exposure in utero disrupts expression of desert hedgehog and insulin-like factor 3 in the developing fetal rat testis." Endocrinology 150.1 (2009): 445-51. Print.

Gray LE Jr, Ostby JS, Kelce WR. 1994. Developmental effects of an environmental antiandrogen: the fungicide vinclo- zolin alters sex differentiation of the male rat. Toxicol
Appl Pharmacol 129:46–52.

Gray LE Jr, Lambright C, Wilson V, Ostby J, Guillette LJ Jr, Wilson E. 2001a. In vivo and in vitro androgenic effects of beta Trenbolone, a potential feed-lot effluent contaminant.SETAC 22nd Annual Meeting, 15 November 2001,Baltimore, Maryland. Abstract. PH070, 334.

Hotchkiss AK, Ostby JS, Vandenburgh JG, Gray LE., Jr. Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat. Environ Health Perspect. 2002;110 Suppl 3:435–439.

Jost A. 1953. Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Rec Prog Horm Res 8:379–418.

Jost A. 1970. Hormonal factors in the sex differentiation of the mammalian fetus. Philos Trans R Soc Lond B Biol Sci 259:119–130.

Kelce WR, Lambright CR, Gray LE Jr, Roberts KP. 1997. Vinclozolin and p,p′-DDE alter androgen-dependent gene expression: in vivo confirmation of an androgen recep- tor-mediated mechanism. Toxicol Appl Pharmacol 142:192–200.

Phoenix C, Goy R, Gerall A, Young W. 1959. Organizational action of prenatally administered testosterone propionateon the tissues mediating mating behavior in the
female guinea pig. Endocrinology 65:369–382.

Wilson JD, Lasnitzki I. 1971. Dihydrotestosterone formation infetal tissues of the rabbit and rat. Endocrinology 89:659–668.

Wolf CJ, LeBlanc GA, Ostby JS, Gray LE Jr. 2000. Characterization of the period of sensitivity of fetal male sexual development to vinclozolin. Toxicol Sci 55:15.

Yamasaki, K. "Effects of in utero through lactational exposure to dicyclohexyl phthalate and p,p'-DDE in Sprague-Dawley rats." Chemicals Evaluations and Research Institute 189.1 (2009): 4-25. Print.