Gestrinone, sold under the brand names Dimetrose and Nemestran among others, is a medication which is used in the treatment of

endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...

. It has also been used to treat other conditions such as

uterine fibroids Uterine fibroids, also known as uterine leiomyomas, fibromyoma or fibroids, are leiomyoma, benign smooth muscle tumors of the uterus, part of the female reproductive system. Most people with fibroids have no symptoms while others may have dysm ...

and

heavy menstrual bleeding Heavy menstrual bleeding (HMB), previously known as menorrhagia or hematomunia, is a menstruation, menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding (AUB). Abnormal uterine bleeding can be caused by stru ...

and has been investigated as a method of

birth control Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth control only be ...

. Gestrinone is used alone and is not formulated in combination with other medications. It is taken

by mouth 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 ...

or in through the vagina.

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of gestrinone include menstrual abnormalities, estrogen deficiency, and

symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

s of

masculinization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is a medical term commonly used in three medical a ...

acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...

seborrhea A sebaceous gland or oil gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in t ...

, breast shrinkage, increased hair growth, and

scalp hair loss Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front h ...

, among others. Gestrinone has a complex

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

, and is characterized as a mixed

progestogen Progestogens, also sometimes written progestins, progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestoge ...

and antiprogestogen, a weak

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

and

anabolic steroid Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...

, a weak

antigonadotropin An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituit ...

, a weak

steroidogenesis inhibitor A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid ho ...

, and a functional

antiestrogen Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inh ...

. Gestrinone was introduced for medical use in 1986. It has been used extensively in

Europe Europe is a continent located entirely in the Northern Hemisphere and mostly in the Eastern Hemisphere. It is bordered by the Arctic Ocean to the north, the Atlantic Ocean to the west, the Mediterranean Sea to the south, and Asia to the east ...

but appears to remains marketed only in a few countries throughout the world. The medication is not available in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

. Due to its

anabolic Anabolism () is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catab ...

effects, the use of gestrinone in competition has been banned by the

International Olympic Committee The International Olympic Committee (IOC; , CIO) is the international, non-governmental, sports governing body of the modern Olympic Games. Founded in 1894 by Pierre de Coubertin and Demetrios Vikelas, it is based i ...

Medical uses

Gestrinone is approved for and used in the treatment of

. It is described as similar in action and effect to

danazol Danazol, sold as Danocrine and other brand names, is a medication used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema and other conditions. It is taken oral administration, by mouth. The use of danazol is ...

, which is also used in the treatment of endometriosis, but is reported to have fewer androgenic

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s in comparison. Gestrinone has also been used to shrink

uterine fibroid Uterine fibroids, also known as uterine leiomyomas, fibromyoma or fibroids, are benign smooth muscle tumors of the uterus, part of the female reproductive system. Most people with fibroids have no symptoms while others may have painful or h ...

s and to reduce

menorrhagia Heavy menstrual bleeding (HMB), previously known as menorrhagia or hematomunia, is a menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding (AUB). Abnormal uterine bleeding can be caused by structural abnorm ...

. Due to its antigonadotropic effects and ability to inhibit

ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...

, gestrinone has been studied as a method of

hormonal birth control Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origin ...

in women. Large studies across thousands of

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eg ...

s have found it to be effective in preventing

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

. However, although effective, the pregnancy rate in the largest study conducted was 4.6 per 100 woman-years, which is too high of a failure rate for the medication to be recommended as a safe method of birth control. The medication has also been investigated as an emergency post-coital contraceptive.

Contraindications

The medication is

contraindicated In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

, during

lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...

, and in patients with severe cardiac,

chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

or liver disease. It is also contraindicated in patients who experienced metabolic and/or vascular disorders during previous estrogen or progestogen therapy, or who are allergic to the medication. The medication is contraindicated in children.

Side effects

The main side effects of gestrinone are

ic and

ic in nature. In one study of 2.5 mg oral gestrinone twice per week in women, it caused

in 71%,

in 65%, breast hypoplasia in 29%,

hirsutism Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a male pattern of hair growth in a female that ma ...

in 9%, and

in 9%. In another study, the rate of androgenic side effects was similarly 50%. Other androgenic side effects that have been reported include

oily skin The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue guarding muscles, bones, ligaments and internal organs. Human skin is similar to most ...

and

hair Hair is a protein filament that grows from follicles found in the dermis. Hair is one of the defining characteristics of mammals. The human body, apart from areas of glabrous skin, is covered in follicles which produce thick terminal and ...

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...

, voice deepening, and clitoral enlargement, the latter two of which as well as hirsutism may be irreversible. Gestrinone also inhibits

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. They are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. T ...

secretion Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mec ...

and causes

amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...

oligomenorrhea Oligomenorrhea is characterised by infrequent menstrual periods. Generally, the menstrual periods occur at intervals of greater than 35 days, with fewer than 9 periods in a year, where previously there had been a regularly established pattern. Th ...

in a high percentage of women. Similarly, circulating

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 ...

levels have been found to be reduced by 50%, which may result in estrogen deficiency and associated

s. Studies of 2.5 mg oral gestrinone twice per week have found a rate of amenorrhea of 50 to 58%, while a study of 5 mg oral gestrinone per day found a rate of amenorrhea of 100%. It has been found that vaginal gestrinone shows fewer androgenic side effects and

than oral gestrinone with equivalent effectiveness in endometriosis. Gestrinone appears to show similar effectiveness to

in the treatment of endometriosis but with fewer side effects, in particular androgenic side effects.

Pharmacology

Pharmacodynamics

The

of gestrinone is complex and multifaceted. It shows high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resi ...

(PR), as well as lower affinity for the

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...

(AR). The medication has mixed

ic and antiprogestogenic activity – that is, it is a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the PR or a

selective progesterone receptor modulator A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor (PR), the biological target of progestogens like progesterone. A characteristic that distinguishes such substances from full receptor agonists ...

(SPRM) – and is a weak

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the AR, or an

anabolic–androgenic steroid Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...

(AAS). Similarly to danazol, gestrinone acts as a weak

via activation of the PR and AR in the

pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...

and suppresses the mid-cycle surge of

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...

(LH) and

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, puberty, pubertal maturat ...

(FSH) during the

without affecting basal levels of these hormones. It also inhibits ovarian

steroidogenesis A steroid is an organic compound with four 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 that alter memb ...

and, via activation of the AR in the

liver 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 ...

, decreases circulating levels of

sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding prot ...

(SHBG), thereby resulting in increased levels of free

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 ...

. In addition to the PR and AR, gestrinone has been found to bind to the

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

(ER) with relatively "avid" affinity. The medication has functional antiestrogenic activity in the

endometrium The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...

. Unlike danazol, gestrinone does not appear to bind to SHBG or

corticosteroid-binding globulin Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6, is a protein produced in the liver in animals. In humans it is encoded by the SERPINA6 gene. It is an alpha-globulin. Function This gene encodes an alpha-globulin ...

(CBG).

Pharmacokinetics

Gestrinone is bound to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

in the circulation. It is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

in the

mainly by

hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

. Four hydroxylated

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

s with reduced activity relative to gestrinone have been found to be formed. The

elimination half-life Biological half-life (elimination half-life, pharmacological 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 blood plasma. ...

of gestrinone is 27.3 hours. The medication is excreted in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

and

bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...

Chemistry

Gestrinone, also known as 17α-ethynyl-18-methyl-19-nor-δ^9,11-testosterone, as well as 17α-ethynyl-18-methylestra-4,9,11-trien-17β-ol-3-one or as 13β-ethyl-18,19-dinor-17α-pregna-4,9,11-trien-20-yn-17β-ol-3-one, is a

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 ...

estrane Estrane is a C18 steroid derivative, with a gonane core. ''Estrenes'' are estrane derivatives that contain a double bond, with an example being nandrolone. ''Estratrienes'' (estrins) are estrane derivatives that contain three double bonds, for i ...

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 ...

and a

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

. It is more specifically a derivative of

norethisterone Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medicatio ...

(17α-ethynyl-19-nortestosterone) and is a member of the

gonane Gonane (cyclopentanoperhydrophenanthrene) is a chemical compound with formula , whose structure consists of four hydrocarbon rings fused together: three cyclohexane units and one cyclopentane. It can also be viewed as the result of fusing a cyc ...

(18-methylestrane) subgroup of the

19-nortestosterone Nandrolone, also known as 19-nortestosterone, is an endogenous androgen. It is also an anabolic steroid (AAS) which is medically used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionat ...

family of progestins. Gestrinone is the C18

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...

derivative of norgestrienone (17α-ethynyl-19-nor-δ^9,11-testosterone) and the δ^9,11 analogue 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, ...

(17α-ethynyl-18-methyl-19-nortestosterone) and is also known as ethylnorgestrienone due to the fact that it is the C13β ethyl variant of norgestrienone. It is also the C17α

ethynyl In organic chemistry, an ethynyl group is a functional group with the formula −C≡CH, representing an acetylene molecule with one fewer hydrogen atom. * Ethynyl group (HC≡C–), also designated as an acetylenic group (from acetylene), is refer ...

and C18 methyl derivative of the AAS

trenbolone Trenbolone is an androgen and anabolic steroid (AAS) of the nandrolone group which itself was never marketed. Trenbolone ester prodrugs, including trenbolone acetate (brand names Finajet, Finaplix, others) and trenbolone hexahydrobenzylcarbonat ...

. The androgenic properties of gestrinone are more exploited in its derivative tetrahydrogestrinone (THG; 17α-ethyl-18-methyl-δ^9,11-19-nortestosterone), a designer steroid which is far more potent as both an AAS and progestogen in comparison. THG was banned by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) in 2003.

History

Gestrinone was introduced for medical use in 1986.

Society and culture

Generic names

''Gestrinone'' is the generic name of the drug and its , , , and . It is also known by its developmental code names ''A-46745'' and ''R-2323'' (or ''RU-2323'').

Brand names

Gestrinone is or has been marketed under the brand names Dimetriose, Dimetrose, Dinone, Gestrin, and Nemestran.

Availability

Gestrinone is or has been marketed in

Australia Australia, officially the Commonwealth of Australia, is a country comprising mainland Australia, the mainland of the Australia (continent), Australian continent, the island of Tasmania and list of islands of Australia, numerous smaller isl ...

Latin America Latin America is the cultural region of the Americas where Romance languages are predominantly spoken, primarily Spanish language, Spanish and Portuguese language, Portuguese. Latin America is defined according to cultural identity, not geogr ...

, and

Southeast Asia Southeast Asia is the geographical United Nations geoscheme for Asia#South-eastern Asia, southeastern region of Asia, consisting of the regions that are situated south of China, east of the Indian subcontinent, and northwest of the Mainland Au ...

, though notably not in the