Gestrinone, sold under the brand names Dimetrose and Nemestran among others, is a medication which is used in the treatment of endometriosis. It has also been used to treat other conditions such as

uterine fibroids Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bl ...

and

heavy menstrual bleeding Heavy menstrual bleeding (HMB), previously known as menorrhagia or hypermenorrhea, 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 abnorma ...

and has been investigated as a method of birth control. 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 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 ...

or in through the vagina.

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of gestrinone include menstrual abnormalities, estrogen deficiency, and symptoms of masculinization like

acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...

seborrhea A sebaceous 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 the greatest numbe ...

, breast shrinkage, increased hair growth, and scalp hair loss, among others. Gestrinone has a complex

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

, and is characterized as a mixed progestogen and

antiprogestogen Antiprogestogens, or antiprogestins, also known as progesterone antagonists or progesterone blockers, are a class of drugs which prevent progestogens like progesterone from mediating their biological effects in the body. They act by blocking the ...

, a 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 ...

and anabolic steroid, 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-pitui ...

, 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 hor ...

, 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 ...

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

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 (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 ...

. Due to its

anabolic Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking ...

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

International Olympic Committee The International Olympic Committee (IOC; french: link=no, Comité international olympique, ''CIO'') is a non-governmental sports organisation based in Lausanne, Switzerland. It is constituted in the form of an association under the Swiss ...

Medical uses

Gestrinone is approved for and used in the treatment of endometriosis. 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 by mouth. The use of danazol is limited by masculin ...

, 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, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s in comparison. Gestrinone has also been used to shrink

uterine fibroid Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bl ...

s and to reduce menorrhagia. Due to its antigonadotropic effects and ability to inhibit

ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...

, 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 origina ...

in women. Large studies across thousands of menstrual cycles have found it to be effective in preventing

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

. 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 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 reason to use a certain tre ...

, 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 proces ...

, and in patients with severe cardiac, chronic kidney disease 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 ...

in 9%, and scalp hair loss 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 mos ...

and hair,

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 w ...

voice deepening A hoarse voice, also known as dysphonia or hoarseness, is when the voice involuntarily sounds breathy, raspy, or strained, or is softer in volume or lower in pitch. A hoarse voice, can be associated with a feeling of unease or scratchiness in the ...

, 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. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...

secretion and causes

amenorrhea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...

oligomenorrhea Oligomenorrhea is infrequent (or, in occasional usage, very light) menstruation. More strictly, it is menstrual periods occurring at intervals of greater than 35 days, with only four to nine periods in a year.thefreedictionary.com > oligomenorrhea ...

in a high percentage of women. Similarly, circulating

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 ...

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

for the progesterone receptor (PR), as well as lower affinity for the androgen receptor (AR). The medication has mixed progestogenic and

ic activity – that is, it is a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

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 (e ...

(SPRM) – and is a weak agonist of the AR, or an anabolic–androgenic steroid (AAS). Similarly to danazol, gestrinone acts as a weak

via activation of the PR and AR in the

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...

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 (GnRH) ...

(LH) and follicle-stimulating hormone (FSH) during the menstrual cycle without affecting basal levels of these hormones. It also inhibits

ovarian The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body ...

steroidogenesis 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 ...

and, via activation of the AR 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 ...

, 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 has also been called androgen ...

(SHBG), thereby resulting in increased levels of free

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 characteristi ...

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

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of the ...

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

(CBG).

Pharmacokinetics

Gestrinone is

bound Bound or bounds may refer to: Mathematics * Bound variable * Upper and lower bounds, observed limits of mathematical functions Physics * Bound state, a particle that has a tendency to remain localized in one or more regions of space Geography *B ...

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

in the circulation. It is

metabolized Metabolism (, from el, μεταβολή ''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 cell ...

in the

mainly by hydroxylation. Four hydroxylated

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 ...

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

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 ...

of gestrinone is 27.3 hours. The medication is

excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

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 ...

and bile.

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

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, fo ...

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. ...

. It is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is a member of the

gonane Gonane is a chemical compound with formula , whose molecule can be described as three molecules or entities of cyclohexane and one of cyclopentane, fused in a particular way. More specifically, the molecule can be described as that of cyclohe ...

(18-methylestrane) subgroup of the 19-nortestosterone family of progestins. Gestrinone is the C18 methyl derivative of

norgestrienone Norgestrienone, sold under the brand names Ogyline, Planor, and Miniplanor, is a progestin medication which has been used in birth control pills, sometimes in combination with ethinylestradiol. It was developed by Roussel Uclaf and has been regis ...

(17α-ethynyl-19-nor-δ^9,11-testosterone) and the δ^9,11 analogue of levonorgestrel (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, the term ethynyl designates a functional group with a double bond with 2 carbon atoms both with sp hybridisation and a triple bond(1 sigma and 2 pi bond) . It is a species similar to acetylene (or in IUPAC ethyne ) with a less ...

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 hexahydrobenzylcarbonate ...

. The androgenic properties of gestrinone are more exploited in its derivative

tetrahydrogestrinone Tetrahydrogestrinone (THG), known by the nickname The Clear, is a synthetic and orally active anabolic–androgenic steroid (AAS) which was never marketed for medical use. It was developed by Patrick Arnold and was used by a number of high-profile ...

(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 respon ...

(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,

Latin America Latin America or * french: Amérique Latine, link=no * ht, Amerik Latin, link=no * pt, América Latina, link=no, name=a, sometimes referred to as LatAm is a large cultural region in the Americas where Romance languages — languages derived f ...

, and

Southeast Asia Southeast Asia, also spelled South East Asia and South-East Asia, and also known as Southeastern Asia, South-eastern Asia or SEA, is the geographical south-eastern region of Asia, consisting of the regions that are situated south of mainlan ...

, though notably not in the