WTF is an Anti-Estrogen and How do They Work?


Aromatase is an enzyme that converts testosterone to estradiol and androstenedione to estrone. Similarly, 17-ketosteroid reductase is an enzyme that is capable of converting androstenedione to testosterone and estrone to estradiol. Aromatase is named based upon the fact that it removes a methyl group on the 19th carbon and rearranges ring A into an aromatic ring, hence it aromatizes the testosterone molecule.

Aromatase is found in many different cells in the body, however it is primarily found in adipose tissue. The liver, skin, and testes are also primary sites of aromatization. In the testes, you have two different cells that respond to the gondaotropic hormones (LH and FSH). Leydig/interstitial cells respond to LH and initiate the synthesis of testosterone. Sertoli/sustentacular cells respond to FSH and initiate and support spermatogenesis. Sertoli cells do not produce testosterone but they contain FSH-dependent aromatase. The estradiol produced in Sertoli cells binds to E2 receptors in Leydig cells and the estradiol will suppress the Leydig cell’s response to LH stimulation. Aromatase activity in other cells are not FSH-dependent. Much of the brain contains aromatase, except the pituitary gland.

Aromatase Regulation

Aromatase is decreased endogenously by prolactin and anti-Mullerian hormone, although AMH is irrelevant and concentrations are almost non-existent in adult males. It is also decreased exogenously by aromatase inhibitors, nicotine, zinc, vitamin E, and resveratrol. The enzyme is increased endogenously by gonadotropins, insulin, testosterone, and androstenedione. Increased adipose tissue increases quantity of aromatase in body.

Aromatase Inhibitors

Aromatase inhibitors (AIs) are medications that are primarily used in the treatment of breast cancer and gynecomastia. AIs inhibit the action of aromatase through competitive inhibition. AIs will bind either reversibly or irreversibly to the active site of aromatase, blocking the binding of testosterone and androstenedione. There are two types of AIs: type I steroidal and type II non-steroidal. Type I AIs bind irreversibly since they are steroid-based and will act as a false substrate for aromatase. Type II AIs bind reversibly by temporary interference with aromatase’s heme group.

Another classification of AIs are generational. First generation AIs like aminoglutethimide inhibited other steroidogenic pathways, reducing glucocorticoid, mineralocorticoid, and thyroid hormone synthesis in the process. These AIs also have a tendency to increase hepatic enzymes. Second generation AIs like fadrozole and formestane are shown to also inhibit the steroidogenic pathway of aldosterone. Currently, third generation AIs are the preferred type since they do not affect steroidogenesis of other steroids. There are three main third generation AIs:

  • Letrozole: Letrozole is a type II non-steroidal AI, so it will bind reversibly. It is shown to have the highest potency of any AI, operating at a 99% degree of potency based off of the degree of inhibition of total body aromatase.

  • Anastrozole: Anastrozole is a type II AI with a 96% degree of potency.

  • Exemestane: Exemestane is a type I steroidal AI, and is the only third generation AI that is type I. Because of this, it will bind irreversibly to aromatase, an action often referred to as suicide inhibition.

Selective Estrogen Receptor Modulators

SERMs are therapeutic agents that shows selectivity of action on estrogen receptors. Can act as antagonist to ERs in bone, liver, and heart. Can act as antagonist to ERs in brain and breast tissue. This can provide the beneficial effects of estrogen in certain tissues while inhibiting the deleterious effects of estrogen in others. There are two distinct estrogen receptors: ER-alpha found primarily in breast tissue and ER-beta found pretty much everywhere else in the body. This selectivity is achieved by the SERMs ability to recruit co-repressors and co-activators (to act as antagonists and agonists, respectively) that can regulate gene expression normally induced by ER activation.

  • Tamoxifen: Tamoxifen acts as an antagonist in breast tissue and agonist in bone. Inhibition of ER receptors in breast tissue has shown to reduce pubertal gynecomastia. It can have a paradoxical effect on hepatic ERs have can affect lipid metabolism which can lead to elevated triglyceride levels. Prolonged use has a hepatotoxic effect. This effect has been implicated in pancreatitis. Tamoxifen has also been shown to cause hepatic steatosis (fatty liver disease) as a result of increase uptake of triglycerides in hepatocytes.

  • Clomifene: Clomifene acts as an antagonist in the hypothalamus. Typically, estradiol binding to ER receptors in the hypothalamus leads to negative feedback inhibition of gonadotropins LH and FSH. Inhibition is shown to increase gonadotropin synthesis. This is why clomifene is recommended as an LH agonist in post-cycle therapy protocols. Because of this effect, clomifene’s intended use is as an ovulation inducer. Clomifene is also used as an off-label replacement for TRT in hypogonadotropic hypogonadic men with fertility concerns since it will not suppress LH and FSH levels. Most common side effect is visual issues. Much like tamoxifen, clomifene can cause hyperlipidemia and hepatic steatosis.

  • Raloxifene: Like tamoxifen, raloxifene acts as an antagonist in breast tissue and agonist in bone. Intended use is to prevent osteoporosis in postmenopausal. Effects and method of action are similar to tamoxifen.

Other Anti-Estrogens

  • Epitiostanol/Methylepitiostanol: Epitiostanol is only bioavailable via injection, however a methylated version marketed as Epistane is able to survive first-pass metabolism. This drug acts as estrogen receptor antagonist and as a weak androgen receptor agonist. Utilized as a steroidal breast cancer therapy in Japan.

  • Drostanolone: Drostanolone is a DHT-derived steroid hormone that is utilized as an anti-estrogenic drug to treat breast cancer. This is the preferred androgen used in the treatment of breast cancer due to the fact it has a low androgenic profile and has a minimal virilizing effect on women.

  • Selective Estrogen Receptor Degraders: SERDs are similar to SERMs, but only act as antagonist to all ERs. Fulvestrant is the most common, however, I have not heard about a practical use as a PED.

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