Demegestone, sold under the brand name Lutionex, is a
progestin
A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural product, natural female sex hormone progesterone in the body. A progestin is a ''synthetic co ...
medication which was previously used to treat
luteal insufficiency
The corpus luteum (Latin for "yellow body"; plural corpora lutea) is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is th ...
but is now no longer marketed.
[http://www.micromedexsolutions.com/micromedex2/] 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 ...
.
Demegestone is a progestin, or a
synthetic progestogen
Progestogens, also sometimes written 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 progestogen in the body. ...
, and hence is an
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of 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 resid ...
, 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
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
.
It has no
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 inc ...
ic activity.
Demegestone was first described in 1966 and was introduced for medical use in
France
France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...
in 1974.
It has only been marketed in France, and has since been discontinued in this country.
Medical uses
Demegestone has been used to treat
luteal insufficiency
The corpus luteum (Latin for "yellow body"; plural corpora lutea) is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is th ...
.
It has also been studied in combination with
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 acti ...
s, such as
moxestrol
Moxestrol, sold under the brand name Surestryl, is an estrogen medication which has been used in Europe for the treatment of menopausal symptoms and menstrual disorders. It is taken by mouth. In addition to its use as a medication, moxestrol has ...
, as an
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 combin ...
and treatment for
infertility
Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...
.
[Hamada H, Nagao H, Toyoda H, Hayashi H, Akihiro L, & Kotaki S (1970). linical observation on oral contraceptive effect by R-2453 (Abstracts of Papers Presented at Showa 44 in the field of gynecology. ''Japanese Journal of Obstetrics and Gynecology-Acta Obstetrica et Gynaecologica Japonica'', 22 (7), 753. https://ci.nii.ac.jp/naid/110002126113/][Levrier, M. (1979, January). Treatment of Ovarian Sterility with Combined Moxestrol-Demegestone Preparation. In Journal De Gynecologie Obstetrique Et Biologie De La Reproduction (Vol. 8, No. 1, Pp. 89–89). 120 Blvd Saint-Germain, 75280 Paris 06, France: Masson Editeur.]
Side effects
Pharmacology
Pharmacodynamics
Demegestone is a
progestogen
Progestogens, also sometimes written 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 progestogen in the body. ...
, and hence is an
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of 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 resid ...
(PR).
It is a highly
potent progestogen, showing 50 times the potency of
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
in the
Clauberg test.
The
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 fertilized ...
-inbhiting dosage of demegestone is 2.5 mg/day, while the
endometrial transformation dosage is 100 mg per cycle.
[Rabe, T., Goeckenjan, M., Ahrendt, H. J., Crosignani, P. G., Dinger, J. C., Mueck, A. O., ... & Strowitzki, T. (2011). Oral Contraceptive Pills: Combinations, Dosages and the Rationale behind 50 Years or Oral Hormonal Contraceptive Development. ''Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology'', 8(1), 58-129. http://www.kup.at/kup/pdf/10166.pdf] The medication is devoid of
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 inc ...
ic activity,
and instead has some
antiandrogen
Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the ...
ic activity.
Demegestone has low
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
glucocorticoid receptor
The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the receptor to which cortisol and other glucocorticoids bind.
The GR is expressed in almost every cell in the body and regulates ...
.
In a particular
bioassay
A bioassay is an analytical method to determine the concentration or potency of a substance by its effect on living animals or plants (''in vivo''), or on living cells or tissues(''in vitro''). A bioassay can be either quantal or quantitative, dir ...
, both demegestone and progesterone showed
antiglucocorticoid
An antiglucocorticoid is a drug which reduces glucocorticoid activity in the body. They include direct glucocorticoid receptor antagonists such as mifepristone and synthesis inhibitors such as metyrapone, ketoconazole, and aminoglutethimide. ...
rather than
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
activity.
The major
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
of demegestone, a 21-
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 hydroxy ...
ated metabolite, is a moderately potent progestogen (4 times the potency of progesterone) and a weak
mineralocorticoid
Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mi ...
(2% of the potency of
deoxycorticosterone Deoxycorticosterone (DOC), or desoxycorticosterone, may refer to:
* 11-Deoxycorticosterone (21-hydroxyprogesterone)
* 21-Deoxycorticosterone (11β-hydroxyprogesterone)
See also
* Deoxycortisol
* Deoxycortisone
* 11-Hydroxyprogesterone
{{Che ...
).
Pharmacokinetics
Demegestone has good
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 ...
.
The initial
volume of distribution
In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...
of demegestone is 31 L.
Demegestone 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 ...
by
hydroxylation
In chemistry, hydroxylation can refer to:
*(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound.
*(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
at the C21, C1, C2, and C11 positions, which is eventually followed by A-ring
aromatization
Aromatization is a chemical reaction in which an aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cyclohexane int ...
after 1,2-
dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
.
The major metabolite of demegestone is a 21-
hydroxy 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. F ...
.
The
metabolic clearance rate of demegestone is 20 L/h.
Its
biological half-lives are 2.39 and 0.24 hours with
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 nutri ...
.
Demegestone and/or its metabolites are
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 ...
, at least in part, 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 excretion, excreted from the body through the urethra.
Cel ...
.
Chemistry
Demegestone, also known as 17α-methyl-δ
9-19-norprogesterone or as 17α-methyl-19-norpregna-4,9-diene-3,20-dione, is a
synthetic norpregnane
19-Norpregnane, also known as 13β-methyl-17β-ethylgonane, is a norsteroid and the 19- demethyl analogue of pregnane. It is the parent compound of 19-norprogesterone (19-norpregn-4-ene-3,20-dione) and derivatives of it such as the progestins ...
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 a ...
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. F ...
of
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
.
It is specifically a combined derivative of
17α-methylprogesterone and
19-norprogesterone, or of
17α-methyl-19-norprogesterone
17α-Methyl-19-norprogesterone (developmental code name H-3510), also known as 17α-methyl-19-norpregn-4-ene-3,20-dione, is a progestin which was never marketed. It is a derivative of progesterone, and is the combined derivative of 17α-methyl ...
.
Related derivatives of 17α-methyl-19-norprogesterone include
promegestone
Promegestone, sold under the brand name Surgestone, is a progestin medication which is used in menopausal hormone therapy and in the treatment of gynecological disorders. It is taken by mouth.
Side effects of promegestone include menstrual ...
and
trimegestone
Trimegestone, sold under the brand names Ondeva and Totelle among others, is a progestin medication which is used in menopausal hormone therapy and in the prevention of postmenopausal osteoporosis. It was also under development for use in birth ...
.
History
Demegestone was first described in the literature in 1964 and was introduced for medical use in 1974 in
France
France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...
.
It was developed by
Roussel Uclaf
Roussel Uclaf S.A. was a French pharmaceutical company and one of several predecessor companies of today's Sanofi.
It was the second largest French pharmaceutical company before it was acquired by Hoechst AG of Frankfurt, Germany in 1997, with p ...
.
Society and culture
Generic names
''Demegestone'' is the
generic name of the drug and its .
It is also known by its developmental code name ''R-2453'' or ''RU-2453''.
Brand names
Demegestone was marketed under the brand name Lutionex.
Availability
Demegestone is no longer marketed and hence is no longer available in any country.
It was previously available in
France
France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...
.
References
{{Navboxes
, title =
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 (fo ...
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, list1 =
{{Androgen receptor modulators
{{Glucocorticoid receptor modulators
{{Progesterone receptor modulators
Abandoned drugs
Antiandrogens
Conjugated dienes
Diketones
Enones
Norpregnanes
Progestogens