THERAPEUTIC USE OF CYPROTERONE ACETATE

Abstract: There is disclosed a new therapeutic use of cyproterone acetate for the manufacture of a medicament for blocking the estrogen signal in the treatment of functional and tumoral estrogen-dependant pathology, in women, caused by intra­ follicular iperestrogenism in a pharmaceutically-acceptable dosage.

Description: The present invention refers to a new therapeutic use of 6-chloro-1α,2α-methylene-17α-hydroxy-4,6-pregnadiene-3,20-dione acetate, well known in the literature as cyproterone acetate, having the following structural formula: The Anti-androgen has been described in the literature activity of cyproterone acetate, for instance by Iunkmann K. et al., Acta endocrinol, suppl. 90, 139-54, 1964; Neumann F. et al, Endocrinology 75, 428-33, 1964; Neumann F. et al. Acta Endocrynol. 53, 382-90, 1966; Kramer M. et al., Naunyn-Schimiedelsbergs Arch. Exp.Path. Pham. 251-124-5, 1965; Neumann F., Medizinische Klinik Wachenscr. fuer klinik und Praxis 68 Jahrgang, Heft 11, 329-333, 1973. Cyproterone acetate as anti-androgen is used in the woman only for the virilization syndromes, such as acne, hirsutism, hypertrichosis: see Rigaud et al. (Hormone Res., 18 , 1983, p.135-142). Rager et al. (Acta Endocr., 74 , 2, 1973, p.399-408) and Kaiser et al. (Gynäkol Prax,4, 1, 1980, p. 47-56) disclose the use of cyproterone acetate as antigonadotropic agent for inhibiting vaginal bleeding in the first, and respectively for contraceptive purposes and for reducing mastodynia in the latter. For the first time, the use of cyproterone acetate as anti-estrogen has been disclosed by the present Applicants in the Italian patent Application 23191 A/80 (corresponding to GB-A-2 080 110 and to U.S. Patent n o 4,344,942) for the treatment of cystic glandular hyperplasia of the endometrium and, in general, of the pathologies caused by extrafollicular (extraovaric) hyperestrogenism (being characteristic of menopause and pre-menopause women, where the term "pre-menopause" obviously means "peri-menopause", i.e. the status immediately prior to the menopausal status) originating from the extrafollicular biosynthesis of estrogens. According to the present invention, it has been surprisingly found that the use of cyproterone acetate may be extended with unexpected results, to other gynecologic pathologies not caused by extrafollicular hyperestrogenism, such as the above cystic glandular hyperplasia of the endometrium. The surprising action of cyproterone acetate consists in inhibiting the intrafollicular estrogen biosynthesis due to the competitive capability to act on the aromatasic system involved in the transformation of testosterone into estrogens taking place in the granulosa which is not directly served by blood supply. More particularly, it has been found according to the present invention that the antiestrogen action of cyproterone acetate not only acts on the menopausal or perimenopausal gynecological pathology caused by extrafollicular hyperestrogenism (such as cystic glandular hyperplasia of the endometrium) but also on other gynecological pathologies wherein the hyperestrogenism responsible for this pathology is "intrafollicular". According to the present invention, the following gynecological pathologies have been treated such as for example: a) fibromatosis and myomatosis of the uterus, b) menometrorrhagia in normal uterus with persistence of proliferative phase of the endometrium and c) fibrocystic mastosis. As illustrated by the following examples, the results so obtained have shown the antiestrogen action of cyproterone acetate on the ovarian cells involved in intrafollicular estrogen biosynthesis. It has been shown that the above pathologies accompanied by hyperestrogenism can be treated with cyproterone acetate, acting directly on the intrafollicular estrogen biosynthesis to obtain: reduction of fibromyomatosis of the uterus, reduction up to the disappearance of myomas of the uterus, reduction of fibromatosis and disappearance of mastodynias and normalization of menometrorrhagic cycle for the persistence of proliferative phase of the endometrium. The important aim reached by the present invention is not that, as expected, of using cyproterone acetate as a progestinic agent on the cells already reached by the estrogen signal, but that of preventing this signal from reaching these cells with a molecule, which is cyproterone acetate, capable of eliminating the estrogen signal. This peculiar antiestrogen action of cyproterone acetate, object of the present invention, shows that this compound, besides the above gynecological pathology, is especially useful in the antiestrogen prevention and therapy of the estrogendependant tumors in women, that is mammary and endometrium tumors. The following examples illustrate the use of cyproterone acetate, its dosages and pharmacological effects according to the invention. In the' following treatments, the compound has been administered by the oral route, at the dose of from 25 to 200 mg/day The dosages used and the number of cycles of treatment depend on the kind of pathology and of the age of the patients to be treated. More precisely, the following dosages have been used: 1) cycles of 50 mg/day from the 13th to the 24th day of the menstrual period in women if the sexual cyclic biorhythm is to be maintained and in the absence of alarm pathology (mammary and endometrium adenocarcinoma, cystic glandular hyperplasia of the endometrium, risky fibromastosis). 2) Cycles of 50 + 50 mg/day 100 + 100 mg/day for a period of 20 days/month (according to the obesity and body surface) in women if the sexual biorhythm is not necessarily to be maintained or in the presence of a risky pathology even in pre-menopause. The therapy is interrupted when the expected results are reached, said results being evaluated on the grounds of the clinical and anamnesial objectiveness, hormonal dosages, echographias, mammographies, thermographies, histologic and cytologic tests. EXAMPLE 1 8 women, aged from 39 to 45, affected with uterine fibromyomatosis were treated with cyproterone acetate. In cases of voluminous fibromyomatosis a normalization was noticed of menstrual flux, if it was menometrorrhagic, together with stabilization of uterus volume during the treatment. In light fibromatosis (10-12 cm diameter), a reduction of about 2 cm of the uterine diameter was noticed. Also in small myomas (3-4 cm diameter), a reduction up to disappearance of myomatous nodus occurred. One case of total disappearance of a 3 cm myomatous nodus after 1 year of therapy with cyproterone acetate, at the dose of 50 mg/day from the 14th to the 24th day of the menstrual period, with pelvic echographic control before and after the treatment, had been previously treated for many months with medroxyprogesterone acetate (MPA) without any positive result. EXAMPLE 2 8 women, aged from 38 to 46, with normal uterine volume and a continuous proliferative phase of the endometrium, suffering from menometrorrhagias , were treated with cyproterone acetate. After a 4-6 months cyclic therapy with 50 mg/day from the 14th to the 24th day, stabilization of the quantity of menstrual flux was obtained and the menometrorrhagia stopped since the first month of treatment. EXAMPLE 3 6 women affected with fibrocystic mastosis were treated with 50 mg of cyproterone acetate from the 14th to the 24th day. During the treatment the disappearance of the mastodynias and mammary tension and, in some cases a remarkable reduction of fibromastosis was noted.

Claims: Use of cyproterone acetate for the manufacture of a medicament for the treatment of functional and tumoral pathology associated to intrafollicular hyperestrogenism. Use according to claim 1 wherein the pathology is uterine fibromatosis and myomatosis. Use according to claim 1 wherein the pathology is menometrorrhagia in the normal uterus with persistence of the proliferative phase of the endometrium and fibrocystic mastosis. Use according to any of claims 1 to 3 wherein the dosage of cyproterone acetate is from 25 mg to 200 mg/day for a number of cycles of treatment which are determined by the pathology being treated and the age of the subject.

Inventors: BLANDAMURA, MANLIO
Applicants: FINCHIMICA S.R.L.
Application year: 1985
Main classification: A61K31
IPC codes: C07J53, A61K31