Allylestrenol was first described in 1958 and was introduced for medical use by 1961.[19][20][21][22] It has been marketed widely throughout the world in the past, but today its availability and usage are relatively limited.[23][6][24][25] It remains available in a few
European countries and in a number of
Asian countries.[23][6][24][25]
Allylestrenol is available in the form of 5 mg
oraltablets.[12][46][47] It is typically used at a dosage of 5 to 40 mg/day.[46][47] In
Japan, a 25 mg allylestrenol oral tablet, under the brand name Perselin, is marketed for the treatment of BPH.[37]
Side effects of allylestrenol are few and have not been well-defined, but are assumed to be similar to those of related medications (i.e., other progestins).[14] When used at high dosages in the treatment of BPH in men, allylestrenol can cause
symptoms of
hypogonadism and
sexual dysfunction.[31][34][35] The medication
indeloxazine may be able to counteract allylestrenol-associated sexual dysfunction.[39] Allylestrenol has no
androgenic or other
off-targethormonal side effects.[31][3][16]
Pharmacology
Pharmacodynamics
Progestogenic and off-target activities
Allylestrenol is a
progestogen, or an
agonist of the
progesterone receptor (PR).[15] It is lacking the
keto group at the C3 position (part of the important 3-keto-4-ene structure) that is common in progestogens and is considered to be necessary for activity, and in relation to this, is thought to be a
prodrug of
17α-allyl-19-nortestosterone (3-ketoallylestrenol).[17][18][50] Allylestrenol is a far less potent progestogen than many other 19-nortestosterone derivatives.[15] The effective
ovulation-inhibiting or
contraceptive dosage of allylestrenol in women has been studied, albeit limitedly.[51] At 20 mg/day allylestrenol, ovulation occurred in 50% of 6 cycles, and at 25 mg/day, ovulation occurred in 0% of 3 cycles.[51][52] The total
endometrial transformation dosage of allylestrenol in women across the cycle is 150 to 250 mg.[53] Unlike virtually all other 19-nortestosterone derivatives, allylestrenol is reported to be a pure progestogen and hence to be devoid of
androgenic,
estrogenic, and
glucocorticoid activity.[3][16] As such, it appears to have properties more similar to those of natural
progesterone.[3][16]
The binding and activity profiles of allylestrenol and its major
active metabolite at
steroid hormone receptors and related
proteins have been studied.[3][17] Allylestrenol has less than 0.2% of the
affinity of
ORG-2058 and less than 2% of the affinity of progesterone for the PR.[3] Similarly, it has less than 0.2% of the affinity of
testosterone for the
androgen receptor (AR), less than 0.2% of the affinity of
estradiol for the
estrogen receptor (ER), less than 0.2% of the affinity of
dexamethasone for the
glucocorticoid receptor (GR), and 0.9% of the affinity of testosterone for
sex hormone-binding globulin (SHBG).[3] Conversely, its
metabolite 17α-allyl-19-nortestosterone has 24% of the affinity of ORG-2058 and 186% of the affinity of progesterone for the PR, 4.5% of the affinity of testosterone for the AR, 9.8% of the affinity of dexamethasone for the GR, and 2.8% of the affinity of testosterone for SHBG, while it similarly has less than 0.2% of the affinity of estradiol for the ER.[3] The affinity of 17α-allyl-19-nortestosterone for the AR was less than that of
norethisterone and
medroxyprogesterone acetate and its affinity for SHBG was much lower than that of norethisterone.[3] These findings may help to explain the absence of
teratogenic effects of allylestrenol on the
external genitalia of female and male rat
fetuses.[3]
Relative affinities (%) of allylestrenol and metabolites
Notes: Values are percentages (%). Reference
ligands (100%) were
P4Tooltip progesterone (medication) for the
PRTooltip progesterone receptor,
TTooltip testosterone (medication) for the
ARTooltip androgen receptor,
E2 for the
ERTooltip estrogen receptor,
DEXATooltip dexamethasone for the
GRTooltip glucocorticoid receptor,
aldosterone for the
MRTooltip mineralocorticoid receptor,
TTooltip testosterone (medication) for
SHBGTooltip sex hormone-binding globulin, and
cortisol for
CBGTooltip Corticosteroid-binding globulin. Sources:[3]
Antigonadotropic effects
Similarly to other progestogens, allylestrenol has potent
antigonadotropic effects.[54] It is able to considerably decrease circulating concentrations of
luteinizing hormone,
testosterone, and
dihydrotestosterone in men.[32][34][39][40] At a dosage of 50 mg/day, allylestrenol has been found to suppress circulating testosterone levels by 78% in men with BPH.[54] This is about the maximum that progestogens are known to be able to suppress testosterone levels in men.[55][56][57] In accordance, the reduction of testosterone and luteinizing hormone levels with allylestrenol in men has been found in a study to be equivalent to that of
chlormadinone acetate and
oxendolone.[33] However, another study found a significantly lower decrease in testosterone levels with 50 mg/day allylestrenol relative to 50 mg/day chlormadinone acetate of about 49–52% versus 76–85%, respectively.[34]Animal research suggests that allylestrenol produces its beneficial effects in BPH via its antigonadotropic effects and consequent suppression of
androgen levels and inhibition of
prostate glandgrowth, similarly to other progestins.[54] Some studies have found that allylestrenol is less effective for BPH than chlormadinone acetate but also produces fewer
side effects and
sexual dysfunction.[31][34][35] Allylestrenol therapy for BPH is associated with a significant decrease in
prostate-specific antigen levels, which may mask the detection of prostate cancer.[54][43]
Other activities
Allylestrenol is not a significant
5α-reductase inhibitor.[54] In one study, it showed about 80,000-fold lower
potency for
inhibition of
5α-reductasein vitro than the established 5α-reductase inhibitor
epristeride (
IC50Tooltip half-maximal inhibitory concentration = 11.3 nM for epristeride and 890 μM for allylestrenol).[54] In another study, there was 70% inhibition of 5α-reductase by allylestrenol at a concentration of 60 μM.[54] This difference may have been due to different experimental conditions, but is still much lower than epristeride.[54]
Allylestrenol is also unique among most 19-nortestosterone progestins in that it lacks the
ketone at the C3 position.[58] It shares this property with
lynestrenol (17α-ethynylestr-4-en-17β-ol),
desogestrel (11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol), and the
anabolic–androgenic steroid (AAS)
ethylestrenol (17α-ethylestr-4-en-17β-ol).[58] Allylestrenol is the C17α allyl and C3 deketo derivative of the AAS
nandrolone (19-nortestosterone), as well as the C17α allyl and C3 deketo
analogue of the AAS
normethandrone (17α-methyl-19-nortestosterone) and
norethandrolone (17α-methyl-19-nortestosterone).[58]
Allylestrenol is the
generic name of the drug and its
INNTooltip International Nonproprietary Name,
BANTooltip British Approved Name, and
JANTooltip Japanese Accepted Name, while allylestrénol is its
DCFTooltip Dénomination Commune Française and allilestrenolo is its
DCITTooltip Denominazione Comune Italiana.[58][25][64][24] The
BANTooltip British Approved Name was originally allyloestrenol, but it was eventually changed.[58][25][24] The medication is also known by its developmental code name SC-6393.[58][25][24]
Brand names
The major brand names of allylestrenol include Gestanin, Gestanon, Perselin, and Turinal.[23][6][24][25][19] It has also been marketed under a variety of other brand names, including Alese, Alilestrenol, Allynol, Allytry, Alynol, Anin, Arandal, Astanol, Cobarenol, Crestanon, Elmolan, Fetugard, Foegard, Fulterm, Gestanin, Gestanin, Gestanol, Gestanyn, Gestin, Geston, Gestormone, Gestrenol, Gravida, Gravidin, Gravinol, Gravion, Gravynon, Gynerol, Gynonys, Iugr, Lestron, Loestrol, Maintane, Meieston, Moresafe, Nidagest, Orageston, Pelias, Preabor, Pregnolin, Pregtenol, Pregular, Prelab, Premaston, Prenolin, Prestrenol, Profar, Progeston, Protanon, and Shegest.[23][6][24][25][19]
^
abcdefghijklThijssen JH (1967). Het metabolisme van progestatieve stoffen (Thesis). Rijksuniversiteit te Utrecht.
^
abcdefghijklmnopqrBergink EW, Loonen PB, Kloosterboer HJ (August 1985). "Receptor binding of allylestrenol, a progestagen of the 19-nortestosterone series without androgenic properties". Journal of Steroid Biochemistry. 23 (2): 165–168.
doi:
10.1016/0022-4731(85)90232-8.
PMID3928974.
^
abSaha A, Roy K, Kakali DE (2000). "Effects of Allylestrenol on Blood Lipids in Relation to its Biological Activity". Indian Journal of Pharmaceutical Sciences. 62 (2): 115.
^
abCortés-Prieto J, Bosch AO, Rocha JA (1980). "Allylestrenol: three years of experience with Gestanon in threatened abortion and premature labor". Clinical Therapeutics. 3 (3): 200–208.
PMID7459930.
^
abKanimoto Y, Okada K (November 1991). "[Antiandrogen therapy of benign prostatic hyperplasia--review of the agents evaluation of the clinical results]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 37 (11): 1423–1428.
PMID1722627.
^
abUmeda K (November 1991). "[Clinical results and problems of anti-androgen therapy of benign prostatic hypertrophy]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 37 (11): 1429–1433.
PMID1722628.
^
abcBorglin NE (1960). "Clinical Evaluation of the Progestational Effect of Allylestrenol". European Journal of Endocrinology. 35 (4 Suppl): NP–S15.
doi:
10.1530/acta.0.XXXVS0NP.
ISSN0804-4643.
^
abcdMadjerek Z, De Visser J, Van Der Vies J, Overbeek GA (September 1960). "Allylestrenol, a pregnancy maintaining oral gestagen". Acta Endocrinologica. 35 (I): 8–19.
doi:
10.1530/acta.0.XXXV0008.
PMID13765069.
^
abcdMcRobb L, Handelsman DJ, Kazlauskas R, Wilkinson S, McLeod MD, Heather AK (May 2008). "Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay". The Journal of Steroid Biochemistry and Molecular Biology. 110 (1–2): 39–47.
doi:
10.1016/j.jsbmb.2007.10.008.
PMID18395441.
S2CID5612000.
^
abcdefZeelen FJ (1990).
Medicinal chemistry of steroids. Elsevier Science Limited. pp. 108–109.
ISBN978-0-444-88727-6. Other examples are allylestrenol (42), a pro-drug converted to the 3-keto analogue (43), which is used in the treatment of threatened abortion [78,79] and altrenogest (44), used in sows and mares to suppress ovulation and estrus behaviour [80]. [...] Progestins with a 17a-allyl side chain: (42) allylestrenol, (43), (44) altrenogest.
^Birkenfeld A, Navot D, Ezra Y, Ron A, Schenker JG (July 1987). "The effect of estradiol valerate and allylestrenol on endometrial transformation in hypergonadotropic hypogonadic women". European Journal of Obstetrics, Gynecology, and Reproductive Biology. 25 (3): 221–229.
doi:
10.1016/0028-2243(87)90102-X.
PMID3609436.
^Barták A, Rozprávka M, Blovský J (October 1992). "[Lynestrenol and allylestrenol in the therapy of postmenopausal hot flushes]". Ceskoslovenska Gynekologie (in Czech). 57 (8): 408–413.
PMID1473164.
^
abYamanaka H, Kosaku N, Makino T, Shida K (September 1983). "[Fundamental and clinical study of the anti-prostatic effect of allylestrenol]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 29 (9): 1133–1145.
PMID6203385.
^Tajima A, Aso Y, Ushiyama T, Hata M, Kambayashi T, Ohmi Y, et al. (March 1986). "[Clinical effect of allylestrenol on benign prostatic hypertrophy]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 32 (3): 477–485.
PMID2425610.
^Kohri K, Kurita T, Iguchi M, Kataoka K (March 1986). "[Clinical effects of allylestrenol on prostatic hypertrophy]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 32 (3): 486–492.
PMID2425611.
^
abcdShida K, Koyanagi T, Kawakura K, Nishida T, Kumamoto Y, Orikasa S, et al. (April 1986). "[Clinical effects of allylestrenol on benign prostatic hypertrophy by double-blind method]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 32 (4): 625–648.
PMID2426932.
^
abOhyama M, Tanifuji T, Haraguchi C, Fujii N, Higaki Y, Yoshida H, Imamura K (April 1986). "[Clinical study of allylestrenol (Org AL-25) on patients with prostatic hypertrophy--transrectal ultrasonography and urodynamic examination]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 32 (4): 649–659.
PMID2426933.
^
abcKatayama T, Umeda K, Kazama T (November 1986). "[Hormonal environment and antiandrogenic treatment in benign prostatic hypertrophy]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 32 (11): 1584–1589.
PMID2435122.
^
abcdefKumamoto Y, Yamaguchi Y, Sato Y, Suzuki R, Tanda H, Kato S, et al. (February 1990). "[Effects of anti-androgens on sexual function. Double-blind comparative studies on allylestrenol and chlormadinone acetate Part I: Nocturnal penile tumescence monitoring]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 36 (2): 213–226.
PMID1693037.
^Tsuji Y, Ariyoshi A, Nakamura H, Michinaga S, Tomita Y, Ohmori A, et al. (August 1992). "[Antiandrogen therapy of benign prostatic hypertrophy: clinical effects of allylestrenol evaluated by transrectal ultrasonographic measurement]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 38 (8): 961–966.
PMID1384295.
^
abFukuoka H, Ishibashi Y, Shiba T, Tuchiya F, Sakanishi S (July 1993). "[Clinical study of allylestrenol (Perselin) on patients with prostatic hypertrophy]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 39 (7): 679–683.
PMID7689782.
^
abIguchi H, Ikeuchi T, Kai Y, Yoshida H (March 1994). "[Influence of anti-androgen therapy for prostatic hypertrophy on lipid metabolism]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 40 (3): 215–219.
PMID7513937.
^Noguchi K, Uemura H, Takeda M, Sekiguchi Y, Ogawa K, Hosaka M (September 2000). "[Rebound of prostate specific antigen after discontinuation of antiandrogen therapy for benign prostatic hyperplasia]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 46 (9): 605–607.
PMID11107528.
^Noguchi K, Takeda M, Hosaka M, Kubota Y (May 2002). "[Clinical effects of allylestrenol on patients with benign prostatic hyperplasia (BPH) evaluated with criteria for treatment efficacy in BPH]". Hinyokika Kiyo. Acta Urologica Japonica (in Japanese). 48 (5): 269–273.
PMID12094708.
^
abNoguchi K, Suzuki K, Teranishi J, Kondo K, Kishida T, Saito K, et al. (July 2006). "Recovery of serum prostate specific antigen value after interruption of antiandrogen therapy with allylestrenol for benign prostatic hyperplasia". Hinyokika Kiyo. Acta Urologica Japonica. 52 (7): 527–530.
PMID16910584.
^Takeuchi H (1981). "The therapeutic effect of concurrent administration of 5-fluorouracil and allylestrenol or hexestrol in small doses on prostatic carcinoma". The Prostate. Supplement. 1: 111–117.
doi:
10.1002/pros.2990020518.
PMID6281750.
S2CID33940589.
^Riquelme Moreno E, Montiel López P, Bravo Guerra R, Escobar Cauz G (July 1972). "[Control of 5 cases of idiopathic precocious puberty with allylestrenol]". Ginecologia y Obstetricia de Mexico (in Spanish). 32 (189): 99–108.
PMID5057420.
^Raithel M, Baenkler HW, Naegel A, Buchwald F, Schultis HW, Backhaus B, et al. (September 2005). "Significance of salicylate intolerance in diseases of the lower gastrointestinal tract". Journal of Physiology and Pharmacology. 56 (Suppl 5): 89–102.
PMID16247191.
^Rozenbaum H (March 1982). "Relationships between chemical structure and biological properties of progestogens". American Journal of Obstetrics and Gynecology. 142 (6 Pt 2): 719–724.
doi:
10.1016/S0002-9378(16)32477-2.
PMID7065053.
^
abEndrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B (December 2011). "Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide". Contraception. 84 (6): 549–557.
doi:
10.1016/j.contraception.2011.04.009.
PMID22078182.
^Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R (June 1980). "Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial". British Journal of Urology. 52 (3): 208–215.
doi:
10.1111/j.1464-410X.1980.tb02961.x.
PMID7000222.
^Knuth UA, Hano R, Nieschlag E (November 1984). "Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men". The Journal of Clinical Endocrinology and Metabolism. 59 (5): 963–969.
doi:
10.1210/jcem-59-5-963.
PMID6237116.
^Sander S, Nissen-Meyer R, Aakvaag A (1978). "On gestagen treatment of advanced prostatic carcinoma". Scandinavian Journal of Urology and Nephrology. 12 (2): 119–121.
doi:
10.3109/00365597809179977.
PMID694436.