Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of

gynecological disorder Gynaecology or gynecology (see spelling differences) is the area of medicine that involves the treatment of women's diseases, especially those of the reproductive organs. It is often paired with the field of obstetrics, forming the combined area ...

s. The medication is available both alone and in combination with an

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

. It is taken

by mouth 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 i ...

. Lynestrenol is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

of progestogens like progesterone. It has weak

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...

ic and

ic activity and no other important

hormonal A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required f ...

activity. The medication is a prodrug of norethisterone in the body, with etynodiol occurring as an intermediate. Lynestrenol was discovered in the late 1950s and was introduced for medical use in 1961. It has mostly been used in

Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a subcontinent of Eurasia and it is located entirel ...

and elsewhere in the world and was never marketed in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...

Medical uses

Lynestrenol is used as a component of

oral contraceptive Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control. Female Two types of female oral contraceptive pill, taken once per day, are widely available: * The combi ...

s in combination with an

and is used in the treatment of

s such as menstrual disorders.

Side effects

Pharmacology

Lynestrenol itself does not bind to the progesterone receptor and is inactive as a progestogen. It is a prodrug, and upon

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 ...

, is rapidly and almost completely converted into norethisterone, a potent progestogen, in the

liver 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 ...

during

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 system ...

. No other metabolites besides norethisterone are formed from lynestrenol. As such, its

pharmacological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

is essentially identical to that of norethisterone. The conversion of lynestrenol into norethisterone is catalyzed by

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...

(28.0%),

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...

(49.8%), and CYP3A4 (20.4%), while other

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s are each responsible for no more than 1.0% of the total conversion. It appears that lynestrenol first undergoes hydroxylation of the C3 position, forming etynodiol as an intermediate, followed by oxygenation of the hydroxyl group to form norethisterone. The peak blood levels are reached within 2 to 4 hours after oral administration, 97% of the administered dose being bound to plasma proteins. Lynestrenol and its metabolites are predominantly excreted in

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

, less in feces,

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

norethisterone

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

being 16 or 17 hours. The pharmacokinetics of lynestrenol have been reviewed.

Chemistry

Lynestrenol, also known as 17α-ethynyl-3-desoxy-19-nortestosterone or as 17α-ethynylestr-4-en-17β-ol, is a synthetic estrane steroid and a

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

of 19-nortestosterone. It differs from norethisterone (17α-ethynyl-19-nortestosterone) and etynodiol (17α-ethynyl-3-deketo-3β-hydroxy-19-nortestosterone) only by the lack of a ketone

group A group is a number of persons or things that are located, gathered, or classed together. Groups of people * Cultural group, a group whose members share the same cultural identity * Ethnic group, a group whose members share the same ethnic ide ...

and

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydro ...

group at the C3 position, respectively.

Synthesis

Chemical syntheses of lynestrenol have been published. In another approach to analogues, nortestosterone (1) is first converted to the di

thioketal In organosulfur chemistry, a thioketal is the sulfur analogue of a ketal (), with one of the oxygen replaced by sulfur (as implied by the ''thio-'' prefix), giving the structure . A dithioketal has ''both'' oxygens replaced by sulfur (). Thio ...

(2) by treatment with dithioglycol in the presence of boron trifluoride. (The mild conditions of this reaction compared to those usually employed in preparing the oxygen ketals probably accounts for the double bond remaining at 4,5). Treatment of this derivative with sodium in liquid ammonia affords the 3-desoxy analog (3). Oxidation by means of

Jones reagent Jones may refer to: People *Jones (surname), a common Welsh and English surname *List of people with surname Jones * Jones (singer), a British singer-songwriter Arts and entertainment * Jones (''Animal Farm''), a human character in George Orwell ...

followed by ethynylation of the 17-ketone leads to the orally active progestin (6). Lynestrenol synthesis

History

Lynestrenol was developed by the

Dutch Dutch commonly refers to: * Something of, from, or related to the Netherlands * Dutch people () * Dutch language () Dutch may also refer to: Places * Dutch, West Virginia, a community in the United States * Pennsylvania Dutch Country People E ...

pharmaceutical company The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate sympto ...

Organon The ''Organon'' ( grc, Ὄργανον, meaning "instrument, tool, organ") is the standard collection of Aristotle's six works on logical analysis and dialectic. The name ''Organon'' was given by Aristotle's followers, the Peripatetics. The six ...

in the late 1950s and was introduced for medical use in 1961. It received a Dutch

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...

for lynestrenol in 1957, and lynestrenol subsequently became a component of ''Lyndiol'', the first Dutch contraceptive pill, in 1962. Around this time, pre- and post-marketing

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s of lynestrenol were conducted, and in 1965, a study consisting of 200 Dutch women was published. Lynestrenol was approved, in the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...

, in combination with mestranol in 1963 and in combination with

ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disord ...

in 1969.

Society and culture

Generic names

''Lynestrenol'' is the generic name of the drug and its , , , and , while ''lynestrénol'' is its and ''linestrenolo'' is its . ''Lynoestrenol'' was formerly the of the drug, but it was eventually changed to ''lynestrenol''.

Brand names

Lynestrenol has been marketed alone as Exluton, Exlutona, and Orgametril, in combination with mestranol as Anacyclin, Lyndiol, Lyndiol 1, Lyndiol 2.5, Nonovul, and Noracycline, and in combination with ethinylestradiol as Anacyclin, Fysioquens, Minilyn, and Ministat, among other formulations and brand names.

Availability

Lynestrenol has been used mainly in

and is also marketed elsewhere throughout the world. The drug was never marketed in the

References

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Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ...

, titlestyle = background:#ccccff , list1 = {{Androgen receptor modulators {{Estrogen receptor modulators {{Progesterone receptor modulators Tertiary alcohols Ethynyl compounds Androgens and anabolic steroids Schering-Plough brands Merck & Co. brands Estranes Prodrugs Progestogens Synthetic estrogens