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General Description:

Estradiol cypionate, identified by CAS number 313-06-4, is a notable compound with significant therapeutic applications. Estradiol Cypionate is a pro-drug ester of , a naturally occurring hormone that circulates endogenously within the human body. Estradiol is the most potent form of all mammalian estrogenic steroids and acts as the major female sex hormone. As a pro-drug of estradiol, estradiol cypionate therefore has the same downstream effects within the body through binding to the Estrogen Receptor (ER) including ERα and ERβ subtypes, which are located in various tissues and organs such as the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%). First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter systemic circulation and exert its estrogenic effects . Esterification of estradiol aims to improve absorption and bioavailability after oral administration (such as with Estradiol Valerate) or to sustain release from depot intramuscular injections (such as with Estradiol Cypionate) through improved lipophilicity. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol. Ester pro-drugs of estradiol are therefore considered to be bioidentical forms of estrogen . Estradiol cypionate is commercially available as Depo-Estradiol, an intramuscular depot injection used for the treatment of moderate to severe vasomotor symptoms associated with menopause and for the treatment of hypoestrogenism due to hypogonadism . The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. However, after menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women . Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. Because of the difference in potency between estradiol and estrone, menopause (and a change in primary hormone from estradiol to estrone) is associated with a number of symptoms associated with this reduction in potency and in estrogenic effects. These include hot flashes, vaginal dryness, mood changes, irregular menses, chills, and sleeping problems. Administration of synthetic and bioidentical forms of estrogen, such as estradiol cypionate, has shown to improve these menopausal symptoms.

Indications:

This drug is primarily indicated for: Depo-Estradiol intramuscular depot injection is indicated for the treatment of moderate to severe vasomotor symptoms and hypoestrogenism due to hypogonadism. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Estradiol cypionate undergoes metabolic processing primarily in: Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Estradiol cypionate are crucial for its therapeutic efficacy: When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Protein Binding:

Estradiol cypionate exhibits a strong affinity for binding with plasma proteins: Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Estradiol cypionate from the body primarily occurs through: Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Estradiol cypionate is distributed throughout the body with a volume of distribution of: The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs . This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Estradiol cypionate exerts its therapeutic effects through: Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Estradiol cypionate functions by: Estradiol enters target cells freely (e.g, female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause and of hypoestrogenism, which are primarily caused by a loss of estrogenic activity. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Classification:

Estradiol cypionate belongs to the class of organic compounds known as steroid esters. These are compounds containing a steroid moiety which bears a carboxylic acid ester group, classified under the direct parent group Steroid esters. This compound is a part of the Organic compounds, falling under the Lipids and lipid-like molecules superclass, and categorized within the Steroids and steroid derivatives class, specifically within the Steroid esters subclass.

Categories:

Estradiol cypionate is categorized under the following therapeutic classes: Adrenal Cortex Hormones, BCRP/ABCG2 Inhibitors, Contraceptive Agents, Female, Contraceptive Agents, Hormonal, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (strength unknown), Cytochrome P-450 CYP1A2 Substrates, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (strength unknown), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 CYP3A7 Substrates, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Drugs that are Mainly Renally Excreted, Estradiol Congeners, Estranes, Estrenes, Estrogen Contraceptives, Estrogens, Fused-Ring Compounds, Gonadal Hormones, Gonadal Steroid Hormones, Hormonal Contraceptives for Systemic Use, Hormones, Hormones, Hormone Substitutes, and Hormone Antagonists, OATP1B1/SLCO1B1 Inhibitors, OCT1 inhibitors, OCT2 Inhibitors, Organic Anion Transporting Polypeptide 2B1 Inhibitors, P-glycoprotein substrates, Reproductive Control Agents, Steroids, Thyroxine-binding globulin inducers, UGT1A1 Substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.