A steroid ester is an

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

of a

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...

. They include

androgen ester An androgen or anabolic steroid ester is an ester of an androgen/anabolic steroid (AAS) such as the natural testosterone or dihydrotestosterone (DHT) or the synthetic nandrolone (19-nortestosterone). Esterification renders AAS into metabolism-res ...

estrogen ester An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification renders estradiol into a prodrug of estrad ...

progestogen ester A progestogen ester is an ester of a progestogen or progestin (a synthetic progestogen). The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, i ...

s, and

corticosteroid ester Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involve ...

s. Steroid esters may be

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...

DHEA sulfate Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepia ...

or synthetic like

estradiol valerate Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and Primiwal E4 and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy fo ...

Esterification In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glyceride ...

is useful because it is often able to render the

parent A parent is a caregiver of the offspring in their own species. In humans, a parent is the caretaker of a child (where "child" refers to offspring, not necessarily age). A ''biological parent'' is a person whose gamete resulted in a child, a male ...

steroid into a prodrug of itself with altered chemical properties such as improved

metabolic stability Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set of ...

water solubility An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, or sodium chloride (NaCl), in water would be re ...

, and/or

lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

. This, in turn, can enhance

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

, for instance by improving the steroid's

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. ...

and/or conferring depot activity and hence an extended duration with

intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, co ...

s with

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

s was developed to prolong the duration of effect of

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). With ...

s. By 1957, more than 500 steroid esters had been synthesized, most frequently of androgens. The longer the fatty acid

chain A chain is a wikt:series#Noun, serial assembly of connected pieces, called links, typically made of metal, with an overall character similar to that of a rope in that it is flexible and curved in compression (physics), compression but line (g ...

, up to a certain optimal length, the longer the duration when prepared as an

oil solution An oil is any nonpolar chemical substance A chemical substance is a form of matter having constant chemical composition and characteristic properties. Some references add that chemical substance cannot be separated into its constituent C ...

and injected. Across a chain length range of 6 to 12 carbon atoms, a length of 9 or 10 carbon atoms ( nonanoate or decanoate ester) was found to be optimal in rodents in the case of testosterone esters. Fatty acid esters increase the

of steroids, with longer fatty acids resulting in greater lipophilicity. The greater

solubility In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solub ...

in oil allows the steroid esters to be dissolved in a smaller oil volume, thereby allowing for larger doses with intramuscular injection. In addition, the greater the lipophilicity of the steroid, as measured by the octanol/water partition coefficient (logP), the slower its release from the oily depot at the injection site and the longer its duration. Steroid esters can also be prepared as

crystalline A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macros ...

aqueous suspension In chemistry, a suspension is a heterogeneous mixture of a fluid that contains solid particles sufficiently large for sedimentation. The particles may be visible to the naked eye, usually must be larger than one micrometer, and will eventually s ...

s. Aqueous suspensions of steroid crystals result in prolongation of duration with intramuscular injection similarly to oil solutions. The duration is longer than that of oil solutions, intermediate between oil solutions and

subcutaneous pellet implant In medicine, a subcutaneous implant, or subcutaneous pellet, is an implant that is delivered under the skin into the subcutaneous tissue by surgery or injection and is used to deliver a drug for a long period of time. Examples of drugs that can ...

s. The sizes of crystals in suspensions varies and can range from 0.1 μm to some hundreds of μm. The duration of crystalline steroid suspensions increases directly with the size of the crystals. However, crystalline suspensions have an irritating effect in the body, and intramuscular injections of crystalline steroid suspensions result in painful local reactions. These reactions worsen with larger crystals, and for this reason, crystal sizes must be limited to minimize local reactions. Particle sizes of more than 300 μg in the case of

estradiol benzoate Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in ...

by intramuscular injection have been found to be too painful for use. In some cases, crystalline steroid suspensions are used not for prolongation of effect, but because the solubility of the steroid result in this preparation being the only practical way to deliver the steroid in a reasonable injection volume. Examples include

cortisone acetate Cortisone acetate (brand names Adreson, Cortison, Cortisone, Cortisone Acetate, Cortone, Cortistab, Cortisyl, others) is a synthetic glucocorticoid corticosteroid and corticosteroid ester which is marketed (under prescription) in many countries ...

and

hydrocortisone Hydrocortisone is the name for the hormone cortisol when supplied as a medication. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, a ...

and its

s. A requirement of long-lasting crystalline steroid administration is that the steroid be sufficiently water-insoluble, so that it dissolves slowly and thereby attains a prolonged therapeutic effect. The crystals in suspensions can sometimes clump together or aggregate and grow in size. This can be avoided by careful formulation. Crystalline suspensions of steroids are prepared either by

precipitation In meteorology, precipitation is any product of the condensation of atmospheric water vapor that falls under gravitational pull from clouds. The main forms of precipitation include drizzle, rain, sleet, snow, ice pellets, graupel and hai ...

or by dispersing finely divided material in an aqueous suspension medium. Desired particle size can be achieved by grinding, for instance through the use of an atomizer.

Adolf Butenandt Adolf Friedrich Johann Butenandt (; 24 March 1903 – 18 January 1995) was a German biochemist. He was awarded the Nobel Prize in Chemistry in 1939 for his "work on sex hormones." He initially rejected the award in accordance with government p ...

reported in 1932 that

estrone benzoate Estrone benzoate, or estrone 3-benzoate, is a synthetic estrogen and estrogen ester – specifically, the C3 benzoate ester of estrone – which was first reported in 1932 and was never marketed. It led to the development in 1933 of the more ...

had a prolonged duration with injection in animals. No such prolongation of action occurred if it was given by

intravenous injection Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

Estradiol benzoate Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in ...

was synthesized in 1933 and was marketed for use the same year.

Sulfur-based esters

Certain

sulfur Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formul ...

-based steroid esters have a sulfamate or

sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactiv ...

moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...

as the ester, typically at the C3 and/or C17β positions. Like many other steroid esters, they are prodrugs. Unlike other steroid esters however, they bypass

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...

with

oral administration Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...

and have high oral

and potency, abolished first-pass

hepatic The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

impact, and long elimination half-lives and durations of action. They are under development for potential clinical use. Examples include the

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

esters estradiol sulfamate (E2MATE; also a potent

steroid sulfatase inhibitor Steroid sulfatase (STS), or steryl-sulfatase (EC 3.1.6.2), formerly known as arylsulfatase C, is a sulfatase enzyme involved in the metabolism of steroids. It is encoded by the ''STS'' gene. Reactions This enzyme catalyses the following chemic ...

) and EC508 (estradiol 17β-(1-(4-(aminosulfonyl)benzoyl)-L-proline)), the

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...

ester

EC586 EC586, also known as testosterone 17β-(1-((5-(aminosulfonyl)-2-pyridinyl)carbonyl)--proline), is an androgen and anabolic steroid which is under development by Evestra for use in androgen replacement therapy in men. It is an orally active andro ...

(testosterone 17β-(1-((5-(aminosulfonyl)-2-pyridinyl)carbonyl)-L-proline)), and sulfonamide esters of

levonorgestrel Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand name Plan B One-Step amon ...

and etonogestrel.

Sulfur-based esters

See also

References

Further reading