What can we do with xenoestrogens?
Xenoestrogen
Xenoestrogens are clinically significant because they can mimic the effects of endogenous estrogen and thus have been implicated in precocious puberty and other disorders of the reproductive system.
Estrogen (medication)
High-dose estrogen therapy is effective in suppressing spermatogenesis and fertility in men, and hence as a male contraceptive. It works both by strongly suppressing gonadotropin secretion and gonadal testosterone production and via direct effects on the testes. After a sufficient course of therapy, only Sertoli cells and spermatogonia remain in the seminiferous tubules of the testes, with a variety of other testicular abnormalities observable. The use of estrogens for contraception in men is precluded by major side effects such as sexual dysfunction, feminization, gynecomastia, and metabolic changes. In addition, there is evidence that with long-term therapy, fertility and gonadal sex hormone production in men may not return following discontinuation of high-dose estrogen therapy.
Phytoestrogen
In addition to interaction with ERs, phytoestrogens may also modulate the concentration of endogenous estrogens by binding or inactivating some enzymes, and may affect the bioavailability of sex hormones by depressing or stimulating the synthesis of sex hormone-binding globulin (SHBG).
Xenin
Xenin is a peptide hormone produced by a subpopulation of chromogranin A-positive endocrine cells in the mucous membrane of the duodenum. The peptide has been found in humans, dogs, pigs, rats, and rabbits.
Xenoestrogen
Phthalates are plasticizers providing durability and flexibility to plastics such as polyvinyl chloride. High molecular weight phthalates are used in flooring, wall coverings and medical device such as intravenous bags and tubing. Low molecular weight phthalates are found in perfumes, lotions, cosmetics, varnishes, lacquers and coatings including timed releases in pharmaceuticals.
Ethinylestradiol
EE is an estrogen similarly to natural estrogens like estradiol and conjugated estrogens (Premarin) and synthetic estrogens like diethylstilbestrol. It binds to and activates both isoforms of the estrogen receptor, ERα and ERβ. In one study, EE was found to have 233% and 38% of the affinity of estradiol for the ERα and ERβ, respectively. In another study, it was found to possess 194% and 151% of the affinity of estradiol for the ERα and ERβ, respectively. EE also appears to signal through the GPER, a membrane estrogen receptor, similarly to estradiol. Estrogens have antigonadotropic effects through activation of the ERα. As a contraceptive, EE acts in concert with a progestin to inhibit the mid-cycle surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) via its antigonadotropic effects, thereby inhibiting folliculogenesis and preventing ovulation and hence the possibility of pregnancy.
Testosterone (medication)
Antiandrogens like cyproterone acetate, spironolactone, and bicalutamide can block the androgenic and anabolic effects of testosterone. Estrogens can reduce the effects of testosterone by increasing the hepatic production and in turn circulating levels of sex hormone-binding globulin (SHBG), a carrier protein that binds to and occupies androgens like testosterone and DHT, and thereby reducing free concentrations of these androgens.
Xenoestrogen
Agencies such as the United States Environmental Protection Agency and the World Health Organization International Programme on Chemical Safety are charged to address these issues.
Xenoestrogen
A 2008 report demonstrates further evidence of widespread effects of feminizing chemicals on male development in each class of vertebrate species as a worldwide phenomenon. 99% percent of over 100,000 recently introduced chemicals are underregulated, according to the European Commission.
Phytoestrogen
A phytoestrogen is a plant-derived xenoestrogen (see estrogen) not generated within the endocrine system, but consumed by eating phytoestrogenic plants. Also called a "dietary estrogen", it is a diverse group of naturally occurring nonsteroidal plant compounds that, because of its structural similarity with estradiol (17-β-estradiol), have the ability to cause estrogenic and/or antiestrogenic effects. Phytoestrogens are not essential nutrients because their absence from the diet does not cause a disease, nor are they known to participate in any normal biological function.
Nonsteroidal estrogen
A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they have gradually fallen out of favor following the discovery of toxicities associated with high-dose DES starting in the early 1970s, and are now almost never used. On the other hand, virtually all selective estrogen receptor modulators (SERMs) are nonsteroidal, with triphenylethylenes like tamoxifen and clomifene having been derived from DES, and these drugs remain widely used in medicine for the treatment of breast cancer among other indications. In addition to pharmaceutical drugs, many xenoestrogens, including phytoestrogens, mycoestrogens, and synthetic endocrine disruptors like bisphenol A, are nonsteroidal substances with estrogenic activity.SERMs like tamoxifen and raloxifene can also be considered to be nonsteroidal estrogens in some tissues.
Antiandrogen
Examples of GnRH agonists include leuprorelin (leuprolide) and goserelin, while an example of a GnRH antagonist is cetrorelix. Estrogens that are or that have been used as antigonadotropins include estradiol, estradiol esters like estradiol valerate, estradiol undecylate, and polyestradiol phosphate, conjugated estrogens, ethinylestradiol, diethylstilbestrol (no longer widely used), and bifluranol. Progestogens that are used as antigonadotropins include chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, and oxendolone.
Xenobiotic
Xenobiotics may be grouped as carcinogens, drugs, environmental pollutants, food additives, hydrocarbons, and pesticides.
Gynecomastia
Medical treatment of gynecomastia is most effective when done within the first two years after the start of male breast enlargement. Selective estrogen receptor modulators (SERMs) such as tamoxifen, raloxifene, and clomifene may be beneficial in the treatment of gynecomastia but are not approved by the Food and Drug Administration for use in gynecomastia. Clomifene seems to be less effective than tamoxifen or raloxifene. Tamoxifen may be used for painful gynecomastia in adults. Aromatase inhibitors (AIs) such as anastrozole have been used off-label for cases of gynecomastia occurring during puberty but are less effective than SERMs. A few cases of gynecomastia caused by the rare disorders aromatase excess syndrome and Peutz–Jeghers syndrome have responded to treatment with AIs such as anastrozole. Androgens/anabolic steroids may be effective for gynecomastia. Testosterone itself may not be suitable to treat gynecomastia as it can be aromatized into estradiol, but nonaromatizable androgens like topical androstanolone (dihydrotestosterone) can be useful.
Ethinylestradiol
EE is a potent functional antiandrogen in both women and men. It mediates its antiandrogenic effects by 1) stimulating the production of sex hormone-binding globulin (SHBG) in the liver, which decreases free and thus bioactive concentrations of testosterone in the blood; and by 2) suppressing luteinizing hormone (LH) secretion from the pituitary gland, which decreases production of testosterone by the gonads. Birth control pills that contain EE are useful in the treatment of androgen-dependent conditions like acne and hirsutism by virtue of their antiandrogenic effects.
Xenoestrogen
Other scientists argue that the observed effects are spurious and inconsistent, or that the quantities of the agents are too low to have any effect. A 1997 survey of scientists in fields pertinent to evaluating estrogens found that 13 percent regarded the health threats from xenoestrogens as "major," 62 percent as "minor" or "none," and 25 percent were unsure.
Testosterone (medication)
Aromatase inhibitors like anastrozole prevent the conversion of testosterone into estradiol by aromatase. As only a very small fraction of testosterone is converted into estradiol, this does not affect testosterone levels, but it can prevent estrogenic side effects like gynecomastia that can occur when testosterone is administered at relatively high dosages. However, estradiol exerts negative feedback on the hypothalamic–pituitary–gonadal axis and, for this reason, prevention of its formation can reduce this feedback and disinhibit gonadal production of testosterone, which in turn can increase levels of endogenous testosterone. Testosterone therapy is sometimes combined with an aromatase inhibitor for men with secondary hypogonadism who wish to conceive children with their partners.
Risk factors for breast cancer
Many xenoestrogens (industrially made estrogenic compounds) and other endocrine disruptors are potential risk factors of breast cancer.
Estrogen (medication)
Testosterone, prasterone (dehydroepiandrosterone; DHEA), boldenone (δ-testosterone), and nandrolone (19-nortestosterone) are naturally occurring androgens/anabolic steroids (AAS) which form estradiol as an active metabolite in small amounts and can produce estrogenic effects, most notably gynecomastia in men at sufficiently high dosages. Similarly, a number of synthetic AAS, including methyltestosterone, metandienone, normethandrone, and norethandrolone, produce methylestradiol or ethylestradiol as an active metabolite in small quantities, and can produce estrogenic effects as well. A few progestins, specifically the 19-nortestosterone derivatives norethisterone, noretynodrel, and tibolone, metabolize into estrogens (e.g., ethinylestradiol) and can produce estrogenic effects as well.
Risk factors for breast cancer
Many xenoestrogens (industrially made estrogenic compounds) are endocrine disruptors, and potential risk factors of breast cancer.
Endocrine disruption is the hypothesis that some chemicals in the body, such as Bisphenol A, are capable of interfering with the production, processing, and transmission of hormones.
Transgender hormone therapy (male-to-female)
Numerous other progestogens and by extension antigonadotropins have been used to suppress testosterone levels in men and are likely useful for such purposes in transgender women as well. Progestogens alone are in general able to suppress testosterone levels in men by a maximum of about 70 to 80%, or to just above female/castrate levels when used at sufficiently high doses. The combination of a sufficient dosage of a progestogen with very small doses of an estrogen (e.g., as little as 0.5–1.5 mg/day oral estradiol) is synergistic in terms of antigonadotropic effect and is able to fully suppress gonadal testosterone production, reducing testosterone levels to the female/castrate range.
Xenoestrogen
The onset of puberty is characterized by increased levels of hypothalamic gonadotropin releasing hormone (GnRH). GnRH triggers the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland, which in turn causes the ovaries to respond and secrete estradiol. Increases in gonadal estrogen promote breast development, female fat distribution and skeletal growth. Adrenal androgen and gonadal androgen result in pubic and axillary hair. Peripheral precocious puberty caused by exogenous estrogens is evaluated by assessing decreased levels of gonadotrophins.
Hormones and Brain Differentiation
Dörner discusses the endocrine system and the effects of castration. According to Dörner, research on animals shows that "the direction of sex drive can be changed, at least in part, by intrahypothalamic sex hormone implantations or hypothalamic lesions." He argues that "an important preventative therapy of sexual differentiation disturbances" could be achieved through "administration of androgens in gonosomal male foetuses with androgen deficiency during the critical differentiation periods of genital organs and, in particular, of the brain." Dörner notes that there are possible arguments against a program to prevent homosexuality, including the fact that "numerous prominent personalities" of the past were homosexuals, including some who were "outstanding poets, painters, or composers." However, he defends his proposal on the grounds that 25% of homosexuals attempt suicide and that "a great number of males and females with inborn sexual deviations are suffering from psychosexual pressure." Dörner writes that he had received letters from unhappy transsexuals and homosexuals, and that in his view the medical profession has a responsibility to ease their suffering.
Sex steroid
Sex steroids, also known as gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and signaling cascades. The term sex hormone is nearly always synonymous with "sex steroid". The polypeptide hormones luteinizing hormone, follicle-stimulating hormone and gonadotropin-releasing hormone are usually not regarded as sex hormones, although they play major sex-related roles.
Estrogen (medication)
High-dose estrogen therapy has been used successfully in the treatment of sexual deviance such as paraphilias in men but has been found to produce many side effects (e.g., gynecomastia, feminization, cardiovascular disease, blood clots) and so is no longer recommended for such purposes. It works by suppressing testosterone levels, similarly to high-dose progestogen therapy and gonadotropin-releasing hormone analogue (GnRH analogue) therapy. Lower dosages of estrogens have also been used in combination with high-dose progestogen therapy in the treatment of sexual deviance in men. High incidence of sexual dysfunction has similarly been associated with high-dose estrogen therapy in men treated with it for prostate cancer.
Testosterone (medication)
Adverse effects may also include minor side effects such as oily skin, acne, and seborrhea, as well as loss of scalp hair, which may be prevented or reduced with 5α-reductase inhibitors. In women, testosterone can produce hirsutism (excessive facial/body hair growth), deepening of the voice, and other signs of virilization. Exogenous testosterone may cause suppression of spermatogenesis in men, leading to, in some cases, reversible infertility. Gynecomastia and breast tenderness may occur with high dosages of testosterone due to peripheral conversion of testosterone by aromatase into excessive amounts of the estrogen estradiol. Testosterone treatment, particularly in high dosages, can also be associated with mood changes, increased aggression, increased sex drive, spontaneous erections, and nocturnal emissions.
Estrogen (medication)
High-dose estrogen therapy with a variety of estrogens such as diethylstilbestrol, ethinylestradiol, polyestradiol phosphate, estradiol undecylate, estradiol valerate, and estradiol has been used to treat prostate cancer in men. It is effective because estrogens are functional antiandrogens, capable of suppressing testosterone levels to castrate concentrations and decreasing free testosterone levels by increasing sex hormone-binding globulin (SHBG) production. High-dose estrogen therapy is associated with poor tolerability and safety, namely gynecomastia and cardiovascular complications such as thrombosis. For this reason, has largely been replaced by newer antiandrogens such as gonadotropin-releasing hormone analogues and nonsteroidal antiandrogens. It is still sometimes used in the treatment of prostate cancer however, and newer estrogens with atypical profiles such as GTx-758 that have improved tolerability profiles are being studied for possible application in prostate cancer.
E-SCREEN
The gain of the number of human breast cancer cell is biologically identic to the rise, in tissues of the genital tract, of the mitotic activity such as the rodent endometrium. In the 1930s, a new screening test called the uterotrophic bioassay was created, but it was not until 1962 that was firstly normalized by an expert committee. This assay quantifies the addition of uterine wet weight or the intensification of uterotrophic response and, additionally, it measures vaginal cornification. The test estimates a chemical’s ability to evoke biological activities in accord with agonists or antagonists of endogenous estrogens (e.g. 17ß-estradiol); nevertheless, its use for agonists investigation is much more ordinary than for antagonist. 
The uterus responds to estrogens in two ways:
The uterus responses in rats and mice can be qualitatively compared.Exposure to estrogens (xenoestrogens) may be also easily assessed in fish, reptiles or birds by measuring their vitellogenin (VTG) plasma levels. An example is that expression of the egg yolk precursor protein vitellogenin can be measured by the E-SCREEN test in juvenile brown trout. Usually, vitellogenin is only produced by female fish, because it is estrogen-dependent. Nevertheless, the synthesis of this protein in males and young fish can also occur, as xenoestrogens can also affect the hepatic receptors and activate it. Hence, a frequently used biomarker of exposure to estrogen active substances in the environment is the measurement of vitellogenin levels in male and juvenile trout.
Isolated 17,20-lyase deficiency
Males and females may be treated with hormone replacement therapy (i.e., with androgens and estrogens, respectively), which will result in normal sexual development and resolve most symptoms. In the case of 46,XY (genetically male) individuals who are phenotypically female and/or identify as the female gender, they should be treated with estrogens instead. Removal of the undescended testes should be performed in 46,XY females to prevent their malignant degeneration, whereas in 46,XY males surgical correction of the genitals is generally required, and, if necessary, an orchidopexy (relocation of the undescended testes to the scrotum) may be performed as well. Namely in genetic females presenting with ovarian cysts, GnRH analogues may be used to control high FSH and LH levels if they are unresponsive to estrogens.
Cyanoketone
Cyanoketone, also known as 2α-cyano-4,4',17α-trimethylandrost-5-en-17β-ol-3-one (CTM), is a synthetic androstane steroid and a steroidogenesis inhibitor which is used in scientific research. On account of its structural similarity to pregnenolone, cyanoketone binds to and acts as a potent, selective, and irreversible inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD), an enzyme that is responsible for the conversion of pregnenolone into progesterone, 17α-hydroxypregnenolone into 17α-hydroxyprogesterone, into androstenedione, and androstenediol into testosterone. As such, cyanoketone inhibits the production of both gonadal and adrenal steroids, including progesterone, androgens, estrogens, and corticosteroids. The drug is too toxic for therapeutic use in humans, and so has been used instead exclusively as a research tool.
Antiandrogen
Androgens increase sex drive, and for this reason, antiandrogens are able to reduce sex drive in men. In accordance, antiandrogens are used in the treatment of conditions of sexual deviance such as hypersexuality (excessively high sex drive) and paraphilias (atypical and sometimes societally unacceptable sexual interests) like pedophilia (sexual attraction to children). They have been used to decrease sex drive in sex offenders so as to reduce the likelihood of recidivism (repeat offenses). Antiandrogens used for these indications include cyproterone acetate, medroxyprogesterone acetate, and GnRH modulators.
Xenobiotic
Microorganisms may be a viable solution to the issue of environmental pollution by the production of xenobiotics; a process known as bioremediation. Microorganisms are able to adapt to xenobiotics introduced into the environment through horizontal gene transfer, in order to make use of such compounds as energy sources. This process can be further altered to manipulate the metabolic pathways of microorganisms in order to degrade harmful xenobiotics under specific environmental conditions at a more desirable rate. Mechanisms of bioremediation include both genetically engineering microorganisms and isolating the naturally occurring xenobiotic degrading microbes. Research has been conducted to identify the genes responsible for the ability of microorganisms to metabolize certain xenobiotics and it has been suggested that this research can be used in order to engineer microorganisms specifically for this purpose. Not only can current pathways be engineered to be expressed in other organisms, but the creation of novel pathways is a possible approach.
List of androgens/anabolic steroids
17α-Ethynylated testosterone derivatives are potent progestins with only very weak androgenic/anabolic activity and are used as oral contraceptives or for the treatment of gynecological conditions in women. They are invariably classified as progestins rather than as AAS. However, these progestins are testosterone derivatives and do have significant androgenic/anabolic activity, sometimes producing acne and other mild androgenic effects in women. Conversely, in men, these drugs may actually have functional antiandrogen effects due to their potent progestogenic and hence antigonadotropic activity and capacity to suppress gonadal testosterone production. = Chemical names that are unverified.
Progestin
The androgenic activity of testosterone-derivative progestins and other progestins that have androgenic activity can be roughly ranked as follows:It should be noted however that the clinical androgenic and anabolic activity of the androgenic progestins listed above is still far lower than that of conventional androgens and anabolic steroids like testosterone and nandrolone esters. As such, they are only generally associated with such effects in women and often only at high dosages. In men, due to their concomitant progestogenic activity and by extension antigonadotropic effects, these progestins can have potent functional antiandrogenic effects via suppression of testosterone production and levels.
On the other hand, some progestins have antiandrogenic activity in addition to their progestogenic activity. These progestins, with varying degrees of potency as antiandrogens, include chlormadinone acetate, cyproterone acetate, dienogest, drospirenone, medrogestone, megestrol acetate, nomegestrol acetate, osaterone acetate (veterinary), and oxendolone. The relative antiandrogenic activity in animals of some of these progestins has been ranked as follows: cyproterone acetate (100%) > nomegestrol acetate (90%) > dienogest (30–40%) ≥ chlormadinone acetate (30%) = drospirenone (30%). Antiandrogenic activity in certain progestins may help to improve symptoms of acne, seborrhea, hirsutism, and other androgen-dependent conditions in women.
Male infertility
Though androgens are absolutely essential for spermatogenesis and therefore male fertility, exogenous testosterone therapy has been found to be ineffective in benefiting men with low sperm count. This is thought to be because very high local levels of testosterone in the testes (concentrations in the seminiferous tubules are 20- to 100-fold greater than circulating levels) are required to mediate spermatogenesis, and exogenous testosterone therapy (which is administered systemically) cannot achieve these required high local concentrations (at least not without extremely supraphysiological dosages). Moreover, exogenous androgen therapy can actually impair or abolish male fertility by suppressing gonadotropin secretion from the pituitary gland, as seen in users of androgens/anabolic steroids (who often have partially or completely suppressed sperm production). This is because suppression of gonadotropin levels results in decreased testicular androgen production (causing diminished local concentrations in the testes) and because FSH is independently critical for spermatogenesis. In contrast to FSH, LH has little role in male fertility outside of inducing gonadal testosterone production.
Nonylphenol
Alkylphenols like nonylphenol and bisphenol A have estrogenic effects in the body. They are known as xenoestrogens. Estrogenic substances and other endocrine disruptors are compounds that have hormone-like effects in both wildlife and humans. Xenoestrogens usually function by binding to estrogen receptors and acting competitively against natural estrogens. Nonylphenol has been shown to mimic the natural hormone 17β-estradiol, and it competes with the endogeous hormone for binding with the estrogen receptors ERα and ERβ. Nonylphenol was discovered to have hormone-like effects by accident because it contaminated other experiments in laboratories that were studying natural estrogens that were using polystyrene tubes.
Levonorgestrel
The primary mechanism of action of levonorgestrel as a progestogen-only emergency contraceptive pill is, according to International Federation of Gynecology and Obstetrics (FIGO), to prevent fertilization by inhibition of ovulation and thickening of cervical mucus. FIGO has stated that: "review of the evidence suggests that LNG [levonorgestreol] ECPs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling." In November 2013, the European Medicines Agency (EMA) approved a change to the label saying it cannot prevent implantation of a fertilized egg.
Antiandrogen
In addition to their antigonadotropic effects, estrogens are also functional antiandrogens by decreasing free concentrations of androgens via increasing the hepatic production of sex hormone-binding globulin (SHBG) and by extension circulating SHBG levels. Combined oral contraceptives containing ethinylestradiol have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%. However, combined oral contraceptives that contain the particularly androgenic progestin levonorgestrel have been found to increase SHBG levels by only 50 to 100%, which is likely because activation of the AR in the liver has the opposite effect of estrogen and suppresses production of SHBG. Levonorgestrel and certain other 19-nortestosterone progestins used in combined oral contraceptives like norethisterone also directly bind to and displace androgens from SHBG, which may additionally antagonize the functional antiandrogenic effects of ethinylestradiol. In men, a study found that treatment with a relatively low dosage of 20 μg/day ethinylestradiol for 5 weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease free testosterone levels, increased total circulating levels of testosterone by 50% (via reduced negative feedback by androgens on the HPG axis).
Risk factors for breast cancer
The elevated incidence of breast cancer in women has been associated with prolonged exposure to high levels of estrogens. Xenoestrogens, such as BPA have the capacity to perturb normal hormonal actions. This study provides evidence of the estrogenic effects of BPA. In this study the human breast epithelial cells MCF-10F were treated with 10-3 M, 10-4 M, 10-5 M and 10-6 M BPA continuously for two weeks. The cells treated with 10-3 M BPA died on the second day of treatment. The concentration of 10-4 M BPA was also toxic for the breast epithelial cells, and they died on the fourth day of treatment. This data indicated that these concentrations of BPA are toxic for MCF-10F cells. After the two-week observation period it was seen that the cells formed a high percentage of duct like structures in collagen. MCF-10F cells treated with 10-5 M and 10-6 M BPA formed a high percentage of solid masses, 27% and 20% respectively. This data indicates that BPA is able to induce neoplastic transformation of human breast epithelial cells. Epigenetic changes are involved in the early stages of cancer initiation by altering ductulogenesis. BPA was able to induce transformation of human breast MCF-10F epithelial cells. After treatment with BPA, the cells produced fewer collagen tubules and more solid masses.
Antiestrogen
Antiestrogens are mainly used as a means of estrogen deprivation therapy in the treatment of ER-positive breast cancer. They are also used to treat infertility, male hypogonadism, and gynecomastia (breast development in men) and are used as a component of hormone replacement therapy for transgender men.
Endocrine disruptor
Alkylphenols are xenoestrogens. The European Union has implemented sales and use restrictions on certain applications in which nonylphenols are used because of their alleged "toxicity, persistence, and the liability to bioaccumulate" but the United States Environmental Protections Agency (EPA) has taken a slower approach to make sure that action is based on "sound science".
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
In recent years some newer approaches to optimizing growth have been researched and are beginning to be used. It is possible to reduce the effects of androgens on the body by blocking the receptors with an antiandrogen such as flutamide and by reducing the conversion of testosterone to estradiol. This conversion is mediated by aromatase and can be inhibited by aromatase blockers such as testolactone. Blocking the effects and conversions of estrogens will allow use of lower doses of glucocorticoids with less risk of acceleration of bone maturation. Other proposed interventions have included bilateral adrenalectomy to remove the androgen sources, or growth hormone treatment to enhance growth.
Sexual fetishism
Antiandrogens and selective serotonin reuptake inhibitors (SSRIs) may be prescribed to lower sex drive. Cyproterone acetate is the most commonly used antiandrogen, except in the United States, where it may not be available. A large body of literature has shown that it reduces general sexual fantasies. Side effects may include osteoporosis, liver dysfunction, and feminization. Case studies have found that the antiandrogen medroxyprogesterone acetate is successful in reducing sexual interest, but can have side effects including osteoporosis, diabetes, deep vein thrombosis, feminization, and weight gain. Some hospitals use leuprorelin and goserelin to reduce libido, and while there is presently little evidence for their efficacy, they have fewer side effects than other antiandrogens. A number of studies support the use of SSRIs, which may be preferable over antiandrogens because of their relatively benign side effects. None of these drugs cure sexual fetishism, but they can make it easier to manage.
Antigonadotropin
An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituitary-gonadal (HPG) axis, and thus a decrease in the levels of the androgen, estrogen, and progestogen sex steroids in the body. Antigonadotropins are used for a variety of purposes, including for the treatment hormonally-sensitive cancers, to delay precocious puberty and puberty in transgender youth, as a form of chemical castration to reduce the sex drives of individuals with hypersexuality or pedophilia, and to treat estrogen-associated conditions in women such as menorrhagia and endometriosis. High-dose antigonadotropin therapy has been referred to as "medical castration".
Hormonal breast enhancement
Androgens, such as testosterone and dihydrotestosterone (DHT), powerfully suppress the action of estrogen in the breasts. At least one way that they do this is by reducing the expression of the estrogen receptor in breast tissue. In women with complete androgen insensitivity syndrome (CAIS), who are completely insensitive to androgens and have only modest levels of estrogen (50 pg/ml), the relatively low levels of estrogen are capable of mediating significant breast development, and the breast sizes of CAIS women, on average, are in fact actually larger than those of non-CAIS women. In males treated with antiandrogens, gynecomastia (enlargement of the breasts in males) and mastodynia (breast tenderness/pain) commonly occur. Antiandrogens, for instance spironolactone, are also known to cause breast enlargement and mastodynia in women. Some examples of widely used and highly-potent antiandrogens include cyproterone acetate and bicalutamide.
Estrogen and neurodegenerative diseases
Estrogen can be divided into four classes: 1) Animal Estrogens that includes estrone (E1), estradiol (E2), and estriol (E3); 2) Plant Estrogens (Phytoestrogens); 3) Fungi Estrogens (Mycoestrogens) and 4) Synthetic Estrogens (xenoestrogens). Xenoestrogens contain a large number of compounds that are synthesized or naturally exist. These estrogens imitate estrogen structure and can be designed to satisfy the need of new drugs. They may have a significant impact on neurodegenerative disease treatment due to their ease of synthesis and targeted specificity.
Pharmacodynamics of estradiol
Estrogens are powerful antigonadotropins at sufficiently high concentrations. By exerting negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis), they are able to suppress the secretion of the gonadotropins, LH and FSH, and thereby inhibit gonadal sex hormone production and circulating sex hormone levels as well as fertility (ovulation in women and spermatogenesis in men). Clinical studies have found that in men treated with them, estrogens can maximally suppress testosterone levels by about 95% or well into the castrate/female range (< 50 ng/dL). This is equivalent to the reduction in testosterone levels achieved by orchiectomy and gonadotropin-releasing hormone analogue (GnRH analogue) therapy, corresponding to a complete shutdown of gonadal testosterone production. In addition, it is greater than that achieved with high-dose progestogens like cyproterone acetate and gestonorone caproate, which can maximally suppress testosterone levels in men by about 75%.
Transgender hormone therapy (female-to-male)
Synthetic anabolic–androgenic steroids (AAS), like nandrolone (as an ester like nandrolone decanoate or nandrolone phenylpropionate), are agonists of the androgen receptor (AR) similarly to testosterone but are not usually used in HRT for transgender men or for androgen replacement therapy (ART) in cisgender men. However, they can be used in place of testosterone with similar effects, and can have certain advantages like less or no local potentiation in so-called androgenic tissues that express 5α-reductase like the skin and hair follicles (which results in a reduced rate of skin and hair-related side effects like excessive body hair growth and scalp hair loss), although this can also be disadvantageous in certain aspects of masculinization like facial hair growth and normal body hair growth). Although many AAS are not potentiated in androgenic tissues, they have similar effects to testosterone in other tissues like bone, muscle, fat, and the voice box. Also, many AAS, like nandrolone esters, are aromatized into estrogens to a greatly reduced extent relative to testosterone or not at all, and for this reason, are associated with reduced or no estrogenic effects (e.g., gynecomastia). AAS that are 17α-alkylated like methyltestosterone, oxandrolone, and stanozolol are orally active but carry a high risk of liver damage, whereas AAS that are not 17α-alkylated, like nandrolone esters, must be administered by intramuscular injection (via which they act as long-lasting depots similarly to testosterone esters) but have no more risk of liver damage than does testosterone.
Xenohormone
The most commonly occurring xenohormones are xenoestrogens, which mimic the effects of estrogen. Other xenohormones include xenoandrogens and xenoprogesterones.
Antiestrogen
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens.
Maternal effect
Strong evidence in rats supports the conclusion that neonatal estrogen exposure plays a role in the development of prostate cancer. Using a human fetal prostate xenograft model, researchers studied the effects of early exposure to estrogen with and without secondary estrogen and testosterone treatment. A xenograft model is a graft of tissue transplanted between organisms of different species. In this case, human tissue was transplanted into rats; therefore, there was no need to extrapolate from rodents to humans. Histopathological lesions, proliferation, and serum hormone levels were measured at various time-points after xenografting. At day 200, the xenograft that had been exposed to two treatments of estrogen showed the most severe changes. Additionally, researchers looked at key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors, and tumor suppressors using a custom PCR array. Analysis of DNA methylation showed methylation differences in CpG sites of the stromal compartment after estrogen treatment. These variations in methylation are likely a contributing cause to the changes in the cellular events in the KEGG prostate cancer pathway that inhibit apoptosis and increase cell cycle progression that contribute to the development of cancer.
Antiandrogen
Antiandrogens, such as cyproterone acetate, have been studied for potential use as male hormonal contraceptives. While effective in suppressing male fertility, their use as monotherapies is precluded by side effects, such as androgen deficiency (e.g., demasculinization, sexual dysfunction, hot flashes, osteoporosis) and feminization (e.g., gynecomastia). The combination of a primary antigonadotropin such as cyproterone acetate to prevent fertility and an androgen like testosterone to prevent systemic androgen deficiency, resulting in a selective antiandrogenic action locally in the testes, has been extensively studied and has shown promising results, but has not been approved for clinical use at this time. Dimethandrolone undecanoate (developmental code name CDB-4521), an orally active dual AAS and progestogen, is under investigation as a potential male contraceptive and as the first male birth control pill.
Gonadotropin-releasing hormone agonist
Various medications can be used to prevent the testosterone flare and/or its effects at the initiation of GnRH agonist therapy. These include antigonadotropins such as progestogens like cyproterone acetate and chlormadinone acetate and estrogens like diethylstilbestrol, fosfestrol (diethylstilbestrol diphosphate), and estramustine phosphate; antiandrogens such as nonsteroidal antiandrogens like flutamide, nilutamide, and bicalutamide; and androgen synthesis inhibitors such as ketoconazole and abiraterone acetate.
Antiandrogen
Androgen synthesis inhibitors are enzyme inhibitors that prevent the biosynthesis of androgens. This process occurs mainly in the gonads and adrenal glands, but also occurs in other tissues like the prostate gland, skin, and hair follicles. These drugs include aminoglutethimide, ketoconazole, and abiraterone acetate. Aminoglutethimide inhibits cholesterol side-chain cleavage enzyme, also known as P450scc or CYP11A1, which is responsible for the conversion of cholesterol into pregnenolone and by extension the production of all steroid hormones, including the androgens. Ketoconazole and abiraterone acetate are inhibitors of the enzyme CYP17A1, also known as 17α-hydroxylase/17,20-lyase, which is responsible for the conversion of pregnane steroids into androgens, as well as the conversion of mineralocorticoids into glucocorticoids. Because these drugs all prevent the formation of glucocorticoids in addition to androgens, they must be combined with a glucocorticoid like prednisone to avoid adrenal insufficiency. A newer drug currently under development for treatment of prostate cancer, seviteronel, is selective for inhibition of the 17,20-lyase functionality of CYP17A1, and for this reason, unlike earlier drugs, does not require concomitant treatment with a glucocorticoid.
Antiestrogen
Antiestrogens include selective estrogen receptor modulators (SERMs) like tamoxifen, clomifene, and raloxifene, the ER silent antagonist and selective estrogen receptor degrader (SERD) fulvestrant, aromatase inhibitors (AIs) like anastrozole, and antigonadotropins including androgens/anabolic steroids, progestogens, and GnRH analogues.
Transgender hormone therapy (male-to-female)
Prior to orchiectomy (surgical removal of the gonads) or sex reassignment surgery, the doses of estrogens used in transgender women are often higher than replacement doses used in cisgender women. This is to help suppress testosterone levels. The Endocrine Society (2017) recommends maintaining estradiol levels roughly within the normal average range for premenopausal women of about 100 to 200 pg/mL. However, it notes that these physiological levels of estradiol are usually unable to suppress testosterone levels into the female range. A 2018 Cochrane review proposal questioned the notion of keeping estradiol levels lower in transgender women, which results in incomplete suppression of testosterone levels and necessitates the addition of antiandrogens, and noted that high-dose parenteral estradiol is known to be safe. The Endocrine Society itself recommends dosages of injected estradiol esters that result in estradiol levels that can markedly exceed the normal female range; for instance, 10 mg per week estradiol valerate by intramuscular injection, with a single such injection resulting in estradiol levels of about 1,250 pg/mL at peak and levels of about 200 pg/mL still after 7 days. Dosages of estrogens can be reduced after an orchiectomy or sex reassignment surgery, when gonadal testosterone suppression is no longer needed.
Cryptorchidism
A karyotype can confirm or exclude forms of dysgenetic primary hypogonadism, such as Klinefelter syndrome or mixed gonadal dysgenesis. Hormone levels (especially gonadotropins and AMH) can help confirm that hormonally functional testes are worth attempting to rescue, as can stimulation with a few injections of human chorionic gonadotropin to elicit a rise of the testosterone level. Occasionally, these tests reveal an unsuspected and more complicated intersex condition.
E-SCREEN
Nevertheless, basic scientific research shows that estrogens (and xenoestrogens) may also exert actions through nonnuclear steroid hormone receptors (e.g., membrane ERs), nonsteroid receptors (e.g., neurotransmitter receptors such as the serotonin receptor, dopamine receptor, norepinephrine receptor), orphan receptors (e.g., aryl hydrocarbon receptor (AhR)), enzymatic pathways involved in steroid biosynthesis and/or metabolism, and numerous other mechanisms that converge upon endocrine and reproductive systems.
Several reports suggest that xenoestrogens are clinically significant because they can mimic the effects of endogenous estrogen and directly or indirectly have been implicated in precocious puberty and other disorders of the reproductive system in wildlife and humans.
High-dose estrogen
Estrogens are agonists of the estrogen receptors (ERs), the biological target of endogenous estrogens such as estradiol. When used in high doses, estrogens are powerful antigonadotropins, strongly inhibiting secretion of the gonadotropins luteinizing hormone and follicle-stimulating hormone from the pituitary gland, and in men are able to completely suppress gonadal androgen production and reduce testosterone levels into the castrate range. This is most of the basis of their use in prostate cancer and benign prostatic hyperplasia. When estradiol or an estradiol ester is used for HDE in men, levels of estradiol of at least approximately 200 pg/mL are necessary to suppress testosterone levels into the castrate range.
Methyltestosterone
Methyltestosterone is or has been used in the treatment of delayed puberty, hypogonadism, cryptorchidism, and erectile dysfunction in males, and in low doses to treat menopausal symptoms (specifically for osteoporosis, hot flashes, and to increase libido and energy), postpartum breast pain and engorgement, and breast cancer in women. It is specifically approved in the United States for the treatment of hypogonadism and delayed puberty in males and the treatment of advanced inoperable breast cancer in females. It was also approved in low doses in combination with esterified estrogens for the treatment of moderate to severe vasomotor symptoms associated with menopause in women in the United States, but this formulation was discontinued and hence is no longer used.
Phytoestrogen
A wide range of beneficial effects of phytoestrogens on the cardiovascular, metabolic, central nervous systems as well as reduction of risk of cancer and post menopausal symptoms have been claimed. However, there is also concern that phytoestrogens may act as endocrine disruptors that adversely affect health. Based on currently available evidence, it is not clear whether the potential health benefits of phytoestrogens outweigh their risks.
Seborrhoeic dermatitis
Systemic antiandrogen therapy should only be used to treat seborrhoea in women, and never in men, as these drugs can result in feminization (e.g., gynecomastia), sexual dysfunction, and infertility in males. In addition, antiandrogens theoretically have the potential to feminize male fetuses in pregnant women, and for this reason, should always be combined with effective contraception in sexually active women who can or may become pregnant.
Xenoestrogen
Xenoestrogens have been implicated in a variety of medical problems, and during the last 10 years many scientific studies have found hard evidence of adverse effects on human and animal health.
Levonorgestrel
Levonorgestrel is a progestogen; that is, an agonist of the progesterone receptor (PR), the main biological target of the progestogen sex hormone progesterone. It is also a weak agonist of the androgen receptor (AR), the main biological target of the androgen sex hormone testosterone. Levonorgestrel has no other important hormonal activity, including no estrogenic, glucocorticoid, or antimineralocorticoid activity. The lack of significant mineralocorticoid or antimineralocorticoid activity with levonorgestrel is in spite of a relatively high affinity for the mineralocorticoid receptor of as much as 75% of that of aldosterone. Due to its progestogenic activity, levonorgestrel has antigonadotropic effects, and is able to suppress fertility and gonadal sex hormone production in both women and men.
Gonadotropin-releasing hormone agonist
GnRH agonists acts as agonists of the GnRH receptor, the biological target of gonadotropin-releasing hormone (GnRH). These drugs can be both peptides and small-molecules. They are modeled after the hypothalamic neurohormone GnRH, which interacts with the GnRH receptor to elicit its biologic response, the release of the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH). However, after the initial "flare" response, continued stimulation with GnRH agonists desensitizes the pituitary gland (by causing GnRH receptor downregulation) to GnRH. Pituitary desensitization reduces the secretion of LH and FSH and thus induces a state of hypogonadotropic hypogonadal anovulation, sometimes referred to as “pseudomenopause” or “medical oophorectomy.” GnRH agonists are able to completely shutdown gonadal testosterone production and thereby suppress circulating testosterone levels by 95% or into the castrate/female range in men.
Breast enlargement supplement
Products typically contain a variety of ingredients of plant or fungal origin. The compounds claimed to be pharmacologically active are typically estrogen mimics (called xenoestrogens; specifically known as phytoestrogens in plants and mycoestrogens in fungi).
Estrogen (medication)
An estrogen is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.
Side effects of estrogens include breast tenderness, breast enlargement, headache, nausea, fluid retention, and edema among others. Other side effects of estrogens include an increased risk of blood clots, cardiovascular disease, and, when combined with most progestogens, breast cancer. In men, estrogens can cause breast development, feminization, infertility, low testosterone levels, and sexual dysfunction among others.
Estrogens are agonists of the estrogen receptors, the biological targets of endogenous estrogens like estradiol. They have important effects in many tissues in the body, including in the female reproductive system (uterus, vagina, and ovaries), the breasts, bone, fat, the liver, and the brain among others. Unlike other medications like progestins and anabolic steroids, estrogens do not have other hormonal activities. Estrogens also have antigonadotropic effects and at sufficiently high dosages can strongly suppress sex hormone production. Estrogens mediate their contraceptive effects in combination with progestins by inhibiting ovulation.
Estrogens were first introduced for medical use in the early 1930s. They started to be used in birth control in combination with progestins in the 1950s. A variety of different estrogens have been marketed for clinical use in humans or use in veterinary medicine, although only a handful of these are widely used. These medications can be grouped into different types based on origin and chemical structure. Estrogens are available widely throughout the world and are used in most forms of hormonal birth control and in all menopausal hormone therapy regimens.
Gonadotropin-releasing hormone agonist
A gonadotropin-releasing hormone agonist (GnRH agonist) is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.
Side effects of GnRH agonists are related to sex hormone deficiency and include symptoms of low testosterone levels and low estrogen levels such as hot flashes, sexual dysfunction, vaginal atrophy, osteoporosis, infertility, and diminished sex-specific physical characteristics. They are agonists of the GnRH receptor and work by increasing or decreasing the release of gonadotropins and the production of sex hormones by the gonads. When used to suppress gonadotropin release, GnRH agonists can lower sex hormone levels by 95% in both sexes.
GnRH was discovered in 1971, and GnRH analogues were introduced for medical use in the 1980s. Their nonproprietary names usually end in "-relin". The most well-known and widely used GnRH analogue is leuprorelin (brand name Lupron). GnRH analogues are available as generic medications. Despite this however, they continue to be very expensive.
Cetrorelix
Cetrorelix (, ), or cetrorelix acetate (, ), sold under the brand name Cetrotide, is an injectable gonadotropin-releasing hormone (GnRH) antagonist. A synthetic decapeptide, it is used in assisted reproduction to inhibit premature luteinizing hormone surges The drug works by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In addition, cetrorelix can be used to treat hormone-sensitive cancers of the prostate and breast (in pre-/perimenopausal women) and some benign gynaecological disorders (endometriosis, uterine fibroids and endometrial thinning). It is administered as either multiple 0.25 mg daily subcutaneous injections or as a single-dose 3 mg subcutaneous injection. The duration of the 3 mg single dose is four days; if human chorionic gonadotropin (hCG) is not administered within four days, a daily 0.25 mg dose is started and continued until hCG is administered.
Antigonadotropin
The most well-known and widely used antigonadotropins are the gonadotropin-releasing hormone (GnRH) analogues (both agonists and antagonists). However, many other drugs have antigonadotropic properties as well, including compounds acting on sex steroid hormone receptors such as progestogens, androgens, and estrogens (due to negative feedback on the HPG axis), as well as steroid synthesis inhibitors such as danazol and gestrinone. Some antigonadotropins have a multimodal action, such as cyproterone acetate, which exerts its effects via acting as an antiandrogen, progestin, and steroid synthesis inhibitor. Since progestins have relatively little effect on sexual differentiation compared to the other sex steroids, potent ones such as medroxyprogesterone acetate and chlormadinone acetate are often used at high doses specifically for their antigonadotropic effects.
Paraphilia
Antiandrogens are used in more severe cases. Similar to physical castration, they work by reducing androgen levels, and have thus been described as chemical castration. The antiandrogen cyproterone acetate has been shown to substantially reduce sexual fantasies and offending behaviors. Medroxyprogesterone acetate and gonadotropin-releasing hormone agonists (such as leuprorelin) have also been used to lower sex drive. Due to the side effects, the World Federation of Societies of Biological Psychiatry recommends that hormonal treatments only be used when there is a serious risk of sexual violence, or when other methods have failed. Surgical castration has largely been abandoned because these pharmacological alternatives are similarly effective and less invasive.
Xenoestrogen
The current literature is inadequate to provide the information we need to assess the extent to which environmental chemicals contribute to precocious puberty. Gaps in our knowledge are the result of limitations in the designs of studies, small sample sizes, challenges to conducting exposure assessment and the few number of chemicals studied. Unfortunately exposure is inferred and not actually measured in available studies. The ability to detect the possible role of chemicals in altering pubertal development is confounded by many nutritional, genetic and lifestyle factors capable of affecting puberty and the complex nature of the reproductive endocrine system. Other research challenges include shifts in exposure levels among populations over time and simultaneous exposures to multiple compounds. Overall the literature does not with certainty support the contention that environmental chemicals or dietary factors are having widespread effects on human sexual development. However data does not refute such a hypothesis either. Accelerated sexual development is plausible in individuals exposed to high concentration of estrogenic substances. There is a concerning steady increase in exposure to a wide variety of xenoestrogens in the industrial world. Further research is needed to assess the impact of these compounds on pubertal development.
Estrogen (medication)
Estrogens have contraceptive effects and are used in combination with progestins (synthetic progestogens) in birth control to prevent pregnancy in women. This is referred to as combined hormonal contraception. The contraceptive effects of estrogens are mediated by their antigonadotropic effects and hence by inhibition of ovulation. Most combined oral contraceptives contain ethinylestradiol or its prodrug mestranol as the estrogen component, but a few contain estradiol or estradiol valerate. Ethinylestradiol is generally used in oral contraceptives instead of estradiol because it has superior oral pharmacokinetics (higher bioavailability and less interindividual variability) and controls vaginal bleeding more effectively. This is due to its synthetic nature and its resistance to metabolism in certain tissues such as the intestines, liver, and uterus relative to estradiol. Besides oral contraceptives, other forms of combined hormonal contraception include contraceptive patches, contraceptive vaginal rings, and combined injectable contraceptives. Contraceptive patches and vaginal rings contain ethinylestradiol as the estrogen component, while combined injectable contraceptives contain estradiol or more typically an estradiol ester.
Norethisterone
Norethisterone is used as a hormonal contraceptive in combination with an estrogen – usually ethinylestradiol (EE) – in combined oral contraceptive pills and alone in progestogen-only pills. Norethisterone has also been shown to be effective in inhibiting leutinizing hormone and follicle-stimulating hormone secretion in men as well. Without these hormones, mature sperm cannot survive in the testes. This means that norethisterone could also be an effective male hormonal contraceptive. Aside from its use as a contraceptive, norethisterone can be used to treat premenstrual syndrome, dysmenorrhea, menorrhagia, irregular menstruation, menopausal symptoms (in combination with estrogen), or to postpone a period. It is also commonly used to help prevent uterine hemorrhage in complicated non-surgical or pre-surgical gynecologic cases and in treating non responsive cyclical mastalgia.
Sex change
Genetic females (with two X chromosomes) with congenital adrenal hyperplasia lack an enzyme needed by the adrenal gland to make the hormones cortisol and aldosterone. Without these hormones, the body produces more androgens. This causes male sex characteristics to appear early (or inappropriately).
Progesterone (medication)
Progesterone is used as a component of feminizing hormone therapy for transgender women in combination with estrogens and antiandrogens. However, the addition of progestogens to HRT for transgender women is controversial and their role is unclear. Some patients and clinicians believe anecdotally that progesterone may enhance breast development, improve mood, and increase sex drive. However, there is a lack of evidence from well-designed studies to support these notions at present. In addition, progestogens can produce undesirable side effects, although bioidentical progesterone may be safer and better tolerated than synthetic progestogens like medroxyprogesterone acetate.
Esterified estrogens
Esterified estrogens (EEs), sold under the brand names Estratab and Menest among others, is an estrogen medication which is used hormone therapy for menopausal symptoms and low sex hormone levels in women, to treat breast cancer in both women and men, and to treat prostate cancer in men. It is formulated alone or in combination with methyltestosterone. It is taken by mouth.
Side effects of EEs include nausea, breast tension, edema, and breakthrough bleeding among others. It is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. EEs are a prodrug mainly of estradiol and to a lesser extent of equilin.
EEs were introduced for medical use by 1970. They are available in only a few countries, such as Chile and the United States. They have also been marketed in Argentina and Switzerland in the past.
Semen quality
Other potential xenoestrogens that have been associated with decreased sperm quality in some studies are bisphenol A, nonylphenol and octylphenol.In addition, "in vitro" studies have observed altered sperm function by the following medications:
Metalloestrogen
Metalloestrogens are a class of inorganic xenoestrogens which can affect the gene expression of human cells responding to estrogen. Effects are related to the physiologic function of estrogen because metalloestrogens have shown affinity for estrogen receptors. Because they can mimic estrogen thus activating the receptor, they are considered harmful and potentially linked with breast cancer.
Transgender hormone therapy (female-to-male)
Antiestrogens (or so-called "estrogen blockers") like aromatase inhibitors (AIs) (e.g., anastrozole) or selective estrogen receptor modulators (SERMs) (e.g., tamoxifen) can be used to reduce the effects of high levels of endogenous estrogen (e.g., breast development, feminine fat distribution) in transgender men. In addition, in those who have not yet undergone or completed epiphyseal closure (which occurs during adolescence and is mediated by estrogen), antiestrogens can prevent hip widening as well as increase final height (estrogen limits height by causing the epiphyses to fuse).
Serenic
Agonists and antagonists of the receptors for the endogenous hormones oxytocin and vasopressin, respectively, have been shown to decrease aggressive behavior in scientific research, implicating them in the normal regulation of pathways involving aggressive behavior in the brain. Certain neurosteroids, such as allopregnanolone, also appear to play a role in the regulation of aggression, including, notably, sexually-dimorphic aggressive behavior. The sex hormones testosterone and estradiol also regulate aggression.
E-SCREEN
The biological effects of estrogens (and xenoestrogens) are mediated through the estrogen receptor (ER). Estrogen receptors, which belong to a large superfamily of nuclear receptors, are transcription factors that induce transcription of target genes after binding to specific DNA sequences in their promoter.
Estrogen and neurodegenerative diseases
Nonsteroidal estrogens include xenoestrogens, phytoestrogens and mycoestrogens. They are very useful in neurodegenerative diseases' therapy when considering about the side effects caused by estradiol. 
As the development of chemical synthesis, it becomes possible for people to construct new molecules. Drug companies can exploit naturally existing compounds and synthetic compounds that have estrogen-like activity to produce patented proprietary drugs, especially the contraceptives. 
Phytoestrogens are plant derived estrogens and have similar structures with 17beta-estradiol thus may cause estrogenic or anti-estrogenic effects.
Transgender hormone therapy (male-to-female)
There are two types of progestogens: progesterone, which is the natural and bioidentical hormone in the body; and progestins, which are synthetic progestogens. There are dozens of clinically used progestins. Certain progestins, namely cyproterone acetate and medroxyprogesterone acetate and as described previously, are used at high doses as functional antiandrogens due to their antigonadotropic effects to help suppress testosterone levels in transgender women. Aside from the specific use of testosterone suppression however, there are no other indications of progestogens in transgender women at present. In relation to this, the use of progestogens in transgender women is controversial, and they are not otherwise routinely prescribed or recommended. Besides progesterone, cyproterone acetate, and medroxyprogesterone acetate, other progestogens that have been reported to have been used in transgender women include hydroxyprogesterone caproate, dydrogesterone, and norethisterone acetate. Progestins in general largely have the same progestogenic effects however, and in theory, any progestin could be used in transgender women.
Hormonal therapy (oncology)
Hormonal therapy in oncology is hormone therapy for cancer and is one of the major modalities of medical oncology (pharmacotherapy for cancer), others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous or external administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones (hormone antagonists). Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.
Estrogen and neurodegenerative diseases
Nonsteroidal estrogens prevalently exist in our environment and have both positive and negative effects on our daily life. But as a possible way to get access to neurodegenerative disease treatment, scientists have developed multiple ways to screen these estrogens and select the ones that have less side effects.
Bipartite recombinant yeast system and dual fluorescence report system are designed to screen these potential chemicals.
E-SCREEN
E-SCREEN is a cell proliferation assay based on the enhanced proliferation of human breast cancer cells (MCF-7) in the presence of estrogen active substances. The E-SCREEN test is a reliable tool to easily and rapidly assess estrogenic activity of suspected xenoestrogens (singly or in combination). This bioassay that measures estrogen-induced increase of the number of human breast cancer cell, which is biologically equivalent to the increase of mitotic activity in tissues of the genital tract, was originally developed by Soto et al.
Nandrolone phenylpropionate
Antiestrogens like aromatase inhibitors (e.g., anastrozole) and selective estrogen receptor modulators (e.g., tamoxifen, raloxifene) can interfere with and prevent the estrogenic effects of NPP. 5α-Reductase inhibitors like finasteride and dutasteride can prevent the inactivation of nandrolone in so-called "androgenic" tissues like the skin, hair follicles, and prostate gland and may therefore considerably increase its androgenic side effects. This is opposite to the case of most other AAS, which are either potentiated by 5α-reductase in such tissues or are not metabolized by 5α-reductase. Antiandrogens like cyproterone acetate, spironolactone, and bicalutamide can block both the anabolic and androgenic effects of NPP.
Estrogen (medication)
Synthetic estrogens, such as 17α-substituted estrogens like ethinylestradiol and its C3 esters and ethers mestranol, quinestrol, and ethinylestradiol sulfonate, and nonsteroidal estrogens like the stilbestrols diethylstilbestrol, hexestrol, and dienestrol, are no longer used in menopausal hormone therapy, owing to their disproportionate effects on liver protein synthesis and associated health risks.
Anabolic steroid
Changes in endogenous testosterone levels may also contribute to differences in myotrophic–androgenic ratio between testosterone and synthetic AAS. AR agonists are antigonadotropic – that is, they dose-dependently suppress gonadal testosterone production and hence reduce systemic testosterone concentrations. By suppressing endogenous testosterone levels and effectively replacing AR signaling in the body with that of the exogenous AAS, the myotrophic–androgenic ratio of a given AAS may be further, dose-dependently increased, and this hence may be an additional factor contributing to the differences in myotrophic–androgenic ratio among different AAS. In addition, some AAS, such as 19-nortestosterone derivatives like nandrolone, are also potent progestogens, and activation of the progesterone receptor (PR) is antigonadotropic similarly to activation of the AR. The combination of sufficient AR and PR activation can suppress circulating testosterone levels into the castrate range in men (i.e., complete suppression of gonadal testosterone production and circulating testosterone levels decreased by about 95%). As such, combined progestogenic activity may serve to further increase the myotrophic–androgenic ratio for a given AAS.
Progestin
Progestogens, similarly to the androgens and estrogens through their own respective receptors, inhibit the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) via activation of the PR in the pituitary gland. This effect is a form of negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis) and takes advantage of the mechanism that the body uses to prevent sex hormone levels from becoming too high. Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic effects, and progestins in sufficiently high amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens as well as inhibit fertility (ovulation in women and spermatogenesis in men).
Ethinylestradiol
Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. It is also occasionally used as a component of menopausal hormone therapy for the treatment of menopausal symptoms in combination with progestins. In the past, EE was widely used alone for various indications such as the treatment of gynecological disorders and prostate cancer. It is usually taken by mouth.
The general side effects of EE include breast tenderness and enlargement, headache, fluid retention, and nausea among others. In men, EE can additionally cause breast development, feminization in general, hypogonadism, and sexual dysfunction. Rare but serious side effects include blood clots, liver damage, and cancer of the uterus.
EE is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. It is a synthetic derivative of estradiol, a natural estrogen, and differs from it in various ways. Compared to estradiol, EE has greatly improved bioavailability when taken by mouth, is more resistant to metabolism, and shows relatively increased effects in certain parts of the body like the liver and uterus. These differences make EE more favorable for use in birth control pills than estradiol, though also result in an increased risk of blood clots and certain other rare adverse effects.
EE was developed in the 1930s and was introduced for medical use in 1943. The drug started being used in birth control pills in the 1960s. Today, EE is found in almost all combined forms of birth control pills and is nearly the exclusive estrogen used for this purpose, making it one of if not the most widely used estrogens.
Esterified estrogens/methyltestosterone
Esterified estrogens/methyltestosterone, sold under brand names such as Covaryx, Eemt, Essian, Estratest, Menogen, and Syntest, is a hormonal preparation that combines esterified estrogens with methyltestosterone in one tablet and is used in menopausal hormone therapy.
Xenointoxication
An example of this strategy is the experimental use of oral ivermectin in humans to kill bed bugs and parasitic worms. This technique has also been used to combat other ectoparasites.
Progestin
A variety of progestins have been studied for use as potential male hormonal contraceptives in combination with androgens in men. These include the pregnanes medroxyprogesterone acetate, megestrol acetate, and cyproterone acetate, the norpregnane segesterone acetate, and the estranes norethisterone acetate, norethisterone enanthate, levonorgestrel, levonorgestrel butanoate, desogestrel, and etonogestrel. The androgens that have been used in combination with these progestins include testosterone, testosterone esters, androstanolone (dihydrotestosterone), and nandrolone esters. Dual androgens and progestins such as trestolone and dimethandrolone undecanoate have also been developed and studied as male contraceptives.
Xenoestrogen
It has been suggested that biphenol A and other xenoestrogens might cause disease to humans and animals. One review suggests that bisphenol A exposure as a result of feasible scenarios could cause disease in humans.
Male infertility
Estrogen, at some concentration, has been found to be essential for male fertility/spermatogenesis. However, estrogen levels that are too high can impair male fertility by suppressing gonadotropin secretion and thereby diminishing intratesticular androgen levels. As such, clomiphene citrate (an antiestrogen) and aromatase inhibitors such as testolactone or anastrozole have shown effectiveness in benefiting spermatogenesis.
Xenoestrogen
Although the physiology of the reproductive system is complex, the action of environmental exogenous estrogens is hypothesized to occur by two possible mechanisms. Xenoestrogens may temporarily or permanently alter the feedback loops in the brain, pituitary, gonads, and thyroid by mimicking the effects of estrogen and triggering their specific receptors or they may bind to hormone receptors and block the action of natural hormones. Thus it is plausible that environmental estrogens can accelerate sexual development if present in a sufficient concentration or with chronic exposure. The similarity in the structure of exogenous estrogens and the estrogens has changed the hormone balance within the body and resulted in various reproductive problems in females. The overall mechanism of action is binding of the exogenous compounds that mimic estrogen to the estrogen binding receptors and cause the determined action in the target organs.
Pheromone
Axillary steroids are produced by the testes, ovaries, apocrine glands, and adrenal glands. These chemicals are not biologically active until puberty when sex steroids influence their activity. The change in activity during puberty suggest that humans may communicate through odors. Several axillary steroids have been described as potential human pheromones: androstadienol, androstadienone, androstenol, androstenone, and androsterone.Further evidence of a role for pheromones in sociosexual behavior comes from two double blind, placebo-controlled experiments. The first from 1998, by Cutler, had 38 male volunteers apply either a "male pheromone" or control odor and record six different sociosexual behaviors over two weeks. This study found an increase in sexual behavior in the pheromone users compared to the control group. The study 2002 by McCoy and Pitino was similar, except that participants were women, not men. Females treated with "female pheromone" reported significant increases in many of the behaviors including "sexual intercourse", "sleeping next to a partner", "formal dates", and "petting/affection/kissing". The researchers believed that pheromones had a positive sexual attractant effect. The third study was performed on 44 postmenopausal women and was published in 2004 by Rako and Friebely in the "Journal of Sex Research". The study confirmed the previous results (McCoy & Pitino, 2002) for reproductive-aged women for the two subjective behaviors studied; weekly averages of informal dating and male approaches were not significantly increased for pheromone users. The study found among postmenopausal women, a significantly greater proportion of those using pheromone than those using placebo showed an increase over their own baseline in intimate sociosexual behaviors.
Management of prostate cancer
Each treatment has disadvantages that limit its use in certain circumstances. Although orchiectomy is a low-risk surgery, the psychological impact of removing the testicles can be significant, and sterility is certain. The loss of testosterone can cause hot flashes, weight gain, loss of libido, enlargement of the breasts (gynecomastia), impotence, penile atrophy, and osteoporosis. GnRH agonists eventually cause the same side effects as orchiectomy but may cause worse symptoms at the beginning of treatment. When GnRH agonists are first used, testosterone surges can lead to increased bone pain from metastatic cancer, so antiandrogens or abarelix is often added to blunt these side effects. Estrogens are not commonly used because they increase the risk for cardiovascular disease and blood clots. In general, the antiandrogens do not cause impotence, and usually cause less loss of bone and muscle mass. Ketoconazole can cause liver damage with prolonged use, and aminoglutethimide can cause skin rashes.
List of drugs banned by WADA
Banned androgenic agents are either anabolic steroids, which increase testosterone and epitestosterone, thereby improving muscle strength and endurance, or beta-2 agonists (see adrenergic beta-agonist). Andro, DHEA, stanozolol, testosterone, and nandrolone, or derivates (see below) are banned anabolic steroids. Beta-2 agonists can act as bronchodilators and increase heart rates, in addition to their mild androgenic effects. Other banned androgenic agents include bambuterol, clenbuterol, salbutamol, tibolone, zeranol, zilpaterol, and selective androgen receptor modulators. While a few of the banned drugs are endogenous, that is they are normally produced in the human body, most of the banned drug are exogenous drugs chemically produced.