A steroid ester is an

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

of a

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

. 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 estradiol ...

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 esters. 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 ...

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

like DHEA sulfate or

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

estradiol valerate Estradiol valerate (EV), sold for use oral administration, by mouth under the brand name Progynova and for use by injection (medicine), injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen (medication), es ...

Esterification In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

is useful because it is often able to render the

parent A parent is either the progenitor of a child or, in humans, it can refer to a caregiver or legal guardian, generally called an adoptive parent or step-parent. Parents who are progenitors are First-degree relative, first-degree relatives and have ...

steroid into a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

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, and/or

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

. 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 describing how the body affects a specific su ...

, 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%. H ...

and/or conferring

depot Depot may refer to: Places * Depot, Poland, a village * Depot Glacier (disambiguation) * Depot Island (disambiguation) * Depot Nunatak * Depot Peak Brands and enterprises * Maxwell Street Depot, a restaurant in Chicago, United States * Of ...

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 hav ...

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 (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...

s with

fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...

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). Wit ...

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 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 but linear, rigid, and load-bearing in tension. A ...

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

oil solution An oil is any nonpolar chemical substance that is composed primarily of hydrocarbons and is hydrophobic (does not mix with water) and lipophilic (mixes with other oils). Oils are usually flammable and surface active. Most oils are unsaturat ...

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 chemical substance, substance, the solute, to form a solution (chemistry), solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form su ...

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, macrosc ...

aqueous suspensions. 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 implants. 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 the ...

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 and

hydrocortisone Hydrocortisone is the name for the hormone cortisol when supplied as a medication. It is a corticosteroid and works as an anti-inflammatory and by immune suppression. Uses include conditions such as adrenocortical insufficiency, adrenogenit ...

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 from clouds due to gravitational pull. The main forms of precipitation include drizzle, rain, rain and snow mixed ("sleet" in Commonwe ...

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 pol ...

reported in 1932 that estrone benzoate in

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 nutr ...

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 the ...

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

Sulfur-based esters

Certain

sulfur Sulfur ( American spelling and the preferred IUPAC name) or sulphur ( Commonwealth spelling) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms ...

-based steroid esters have a sulfamate or

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

moiety Moiety may refer to: __NOTOC__ Anthropology * Moiety (kinship), either of two groups into which a society is divided ** A division of society in the Iroquois societal structure in North America ** An Australian Aboriginal kinship group ** Native Ha ...

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 at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

with

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

and have high oral

and

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

, abolished first-pass

hepatic The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

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 called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

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 male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

ester EC586 (testosterone 17β-(1-((5-(aminosulfonyl)-2-pyridinyl)carbonyl)-L-proline)), and sulfonamide esters of

levonorgestrel Levonorgestrel is a hormonal medication 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 names Plan B One-Step and Julie, ...

and

etonogestrel Etonogestrel is a medication which is used as a means of birth control for women. It is available as an implant placed under the skin of the upper arm under the brand names Nexplanon and Implanon. It is a progestin that is also used in combinat ...

Sulfur-based esters

See also

References

Further reading