Composition for use in the treatment of perimenopausal and post-menopausal symptomatology and in the combined hormonal contraceptive treatment

Abstract

The composition for use in the treatment of perimenopausal and post-menopausal symptomatology, comprising a combination of at least one GnRH receptor antagonist with at least one of: - an estrogenic hormone; - a progestin hormone - a selective modulator of estrogen hormone receptors.

Description

[0001] COMPOSITION FOR USE IN THE TREATMENT OF PERIMENOPAUSAL AND POST-MENOPAUSAL

[0002] SYMPTOMATOLOGY AND IN THE COMBINED HORMONAL CONTRACEPTIVE TREATMENT

[0003] Technical Field

[0004] The present invention relates to a composition for use in the treatment of perimenopausal and post-menopausal symptomatology and in the combined hormonal contraceptive treatment.

[0005] Background Art

[0006] As is well known, the period following a patient’s menopause onset is characterized by a number of disorders affecting various physical and psychological aspects.

[0007] In detail, perimenopausal and post-menopausal symptomatology mainly results in vasomotor disturbances such as hot flashes in the face, neck, chest; sweating, chills, dizziness, nausea, headache, palpitations. In addition to these, there are other symptoms related to genitourinary dystrophic-atrophic pathology, changes in osteoarticular and skin trophism, psychological changes, weight changes and possible cardiovascular complications.

[0008] To reduce these disorders, the administration of the so-called hormone replacement therapy (HRT) is widespread.

[0009] In fact, such therapy acts as a replacement for estrogen and progesterone, the female reproductive hormones that are no longer synthesized by the ovaries during menopause.

[0010] Administration of these hormones by HRT therapy results in cessation or reduction of the symptoms just described.

[0011] However, such therapy is not without side effects, especially during the very first few months of taking it.

[0012] It should be pointed out, in fact, that such therapies must be started at least 12 months after the disappearance of the last menstruation.

[0013] In particular, in the first few months, the most common side effect due to HRT therapy is abnormal uterine bleeding, which develops in up to 80% of patients. It is easy to see how such bleeding causes upset in the patient, thus leading to permanent and premature discontinuation of HRT therapy itself.

[0014] In particular, it is ascertained that this side effect develops more frequently where HRT is administered abruptly at the onset of menopause or in perimenopause due to the persistence of ovarian hormone fluctuations.

[0015] Similar disorders are seen in younger patients on combined estro-progestin hormonal contraceptive treatment, particularly as with HRT in the first 3-6 months of use.

[0016] In particular, combined hormonal contraceptives in the first few months of taking them cause side effects such as headache and nausea, which are compounded by the typical complaints of HRT therapy, namely unpredictable menstrual discharge and spotting.

[0017] Thus, there is a particular need to develop new compositions for use in the treatment of perimenopausal and post-menopausal symptoms and combined hormonal contraceptive treatment aimed at reducing the immediate side effects in the first few months of intake that often result in almost immediate abandonment of the therapies themselves.

[0018] Description of the Invention

[0019] The main aim of the present invention is to devise a composition for use in the treatment of perimenopausal and post-menopausal symptomatology and in the combined hormonal contraceptive treatment which allows greatly reducing the side effects in the first few months of taking HRT and combined hormonal contraceptive therapy, such as unpredictable bleeding, headache, nausea and bloating, while greatly increasing patients’ compliance with such hormonal treatments.

[0020] Another object of the present invention is to devise a composition for use in the treatment of perimenopausal and post-menopausal symptomatology and in the combined hormonal contraceptive treatment which allows significantly reducing the risks related to thromboembolism, heart attack, stroke and breast cancer development and which allows the aforementioned drawbacks of the prior art to be overcome within the framework of a simple, rational, easy and efficient to use, as well as cost-effective solution.

[0021] The aforementioned objects are achieved by this composition for use in the treatment of perimenopausal and post-menopausal symptomatology and in the combined hormonal contraceptive treatment having the characteristics of claim 1.

[0022] Embodiments of the Invention

[0023] The present invention relates to a composition for use in the treatment of perimenopausal and post-menopausal symptomatology and in the combined hormonal contraceptive treatment comprising a combination of at least one GnRH receptor antagonist with at least one of: an estrogenic hormone; a progestin hormone; a selective modulator of estrogen hormone receptors.

[0024] The GnRH receptor antagonist is selected from the list comprising: 4-[[(lR)-2- [5-(2-fhiorine-3-methoxyphenyl)-3-[[2-fluorine-6- (tiifhioromethyl)phenyl]methyl] -4-methyl-2, 6-dioxypyrimidin- 1 -yl] - 1 - phenylethyl]amino]butanoic acid (Elagolix) or a pharmaceutically acceptable salt thereof, l-[4-[l-[(2, 6-difluorophenyl) methyl] -5 -[(dimethylamine) methyl]-3-(6- methoxypyridazin-3-yl)-2, 4 dioxytiene [2, 3-d ] pyrimidin-6-yl] phenyl] -3- methoxyurea (Relugolix) or a pharmaceutically acceptable salt thereof, 5- carboxy-3-[2-fluorine-5-(2,3-difluorine-6-methoxybenzyloxy)-4- methoxyphenyl] thiene[3,4-d ] pyrimidine-2,4 (1H, 3H)-dione (Linzagolix) or a pharmaceutically acceptable salt thereof.

[0025] Estrogen hormone is selected from the list comprising: (8R,9S,13S,14S,17R)-17- ethinyl- 13-metyl-7,8,9, 11,12, 14, 15, 16-octahydro-6H- cyclopenta[a]phenanthren-3, 17-diol (Ethinyl-estradiol), (8R,9S, 13S, 14S, 17S)- 13-metyl-6,7,8,9, 11, 12, 14, 15, 16, 17-decahydrocyclopenta[a]phenanthren-3, 17- diol (Estradiol), Estra-l,3,5(10)-trien-3,17b-diol hemihydrate (Estradiol hemihydrate), [(8R,9S, 13S, 14S, 17S)-3-hydroxy-13-methyl-

[0026] 6,7, 8,9, 11, 12, 14, 15, 16, 17-deca-hydrocyclopenta[a]phenantren- 17-yl] pentanoate (Estradiol valerate), (8R,9S,13S,14S,15R,16R,17R)-13-methyl- 6.7.8.9.11.12.14.15.16.17 -deca-hy drocy cl openta[a]phenanthren -3 ,15, 16,17- tetrol (Estetrol), (8R,9S,13S,14S,16R,17R)-13-methyl-

[0027] 6.7.8.9.11.12.14.15.16.17-decahydrocyclopenta[a]phenanthren-3, 16, 17-triol (Estriol), Equine conjugated estrogens.

[0028] The progestin hormone is selected from the list comprising: [(8R,9S, 10R, 13S, 14S, 17R)-17-acetyl-6-chlorine-10, 13-dimethyl-3-oxy-

[0029] 2.8.9.11.12.14.15.16-octahydron - lH-cyclopenta[a]phenantren- 17-yl] acetate

[0030] (Chlormadinone acetate), (8S,9S, 10R, 13S,14S, 17R)- 13-ethyl- 17-ethynyl- 11- methylen- 1,2, 3, 6, 7, 8, 9, 10, 12, 14, 15, 16-dodecahydrocyclopenta[a]phenanthren- 17-ol (Desogestrel), [(170)-17-Hydroxy-3-oxoestra-4,9-dien-17-yl]acetonitryl (Dienogest), (6R,7R,8R,9S, 10R, 13S, 14S, 15S, 16S, 17S)-

[0031] 1,3', 4', 6, 6a, 7, 8, 9, 10, 11, 12, 13, 14, 15, 15a, 16- hexadecahydro- 10, 13- dimethylspiro- [17H-dicyclopropa-6,7: 15,16]cyclopenta [a]phenanthren 17,2'(5H)-furan]-3,5'(2H)-dione) (Drospirenone), (8S,9R, 10S, 13S, 14S, 17R)-13- Ethyl- 17-ethynyl- 17-hydroxy- 1 l-methylidene-2,6,7,8,9, 10, 12, 14, 15, 16- decahydro- lH-cyclopenta[a]phenantren-3-on (Etonogestrel),

[0032] (8R,9S, 10R, 13S, 14S,17R)-13-Ethyl-17-ethynyl-17-hydroxy-

[0033] 1,2, 6, 7, 8, 9, 10, 11,12, 14-deca-hydrocyclopenta[a]phenantren-3-on (Gestodene), (-)-3 -ethyl- 17-ethynyl- 17-hydroxy- 1,2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17- tetradecahydrocyclopenta phenanthren-3-on (Levonorgestrel),

[0034] [(8R,9S,10R,13S,14S,17R)-17-acetyl-13-methyl-16-methylidene-3-oxo- 2,6,7,8,9,10,11,12,14,15 -decahydro- lH-cyclopenta[a]phenanthren- 17-yl] acetate (Nestorone), (6S,8R,9S, 10R, 13S, 14S,17R)-17-acetyl-17-hydroxy- 6, 10, 13-trimethyl-2,6,7,8,9, 11,12, 14, 15, 16-decahydro-lH- cyclopenta[a]phenanthren-3-on (Medroxyprogesterone acetate), [(8S,9S, 10R, 13S, 14S, 17R)-17-acetyl-6, 13-dimethyl-3-oxo-

[0035] 1.2.8.9.10.11.12.14.15.16-decahydrocyclopenta [a]phenanthren- 17-yl] acetate (Nomegestrol Acetate), (8R,9S,10R,13S,14S,17R)-13-ethyl- 17-ethynyl- 17- hydroxy- 1,2, 6, 7, 8, 9, 10, 11, 12, 14-decahydrocyclopenta[a]phenantren-3-on

[0036] (N orelgestromin), (8R, 9S , 1 OR, 13 S , 14S , 17R)- 17-ethynyl- 17 -hydroxy- 13 -metyl-

[0037] 1.2.6.7.8.9.10.11.12.14.15.16- dodecahydrocyclopenta[a]phenantren-3-on (Norethisterone acetate), (13-etil-17-ethynyl-3-hydroxymmino

[0038] 1.2.6.7.8.9.10.11.12.14.15.16- dodecahydrocyclopenta[a] phenanthren-17-yl) acetate (Norgestimate), 6-chlorine- lb,2b-dihydro- 17-hydroxy-3'H- cyclopropa[l,2]pregna-l, 4, 6-triene-3, 20-dione 17-acetate (Cyproterone acetate), 4-Pregnene-3, 20-dione (Progesterone), 9b, 10a-pregna-4,6-dien-3, 20-dione (Dy droge sterone) .

[0039] Selective modulator of estrogen hormone receptors is selected from the list comprising: (7R,8R,9S, 13S, 14S,17R)-17-ethynyl-17-hydroxy-7, 13-dimetyl-

[0040] 1.2.4.6.7.8.9.11.12.14.15.16-dodecahydrocyclopenta[a]phenantren-3-on (Tibolone), l-[[4-[2-(azepan-l-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)- 3-methylindol-5-ol (Bazedoxifene); [6-hydroxy-2-(4-hydroxyphenyl)-l- benzothiophen-3-yl]-[4-(2-piperidin-l-ilethoxy]phenyl]methanone (Raloxifene). Preferably, the combination comprises separate dosages that are co-administered. This means that the combination may comprise different dosages of the GnRH receptor antagonist, estrogen hormone, progestin hormone or selective modulator of estrogen hormone receptor being administered together.

[0041] In this regard, it should be noted that the composition is administered orally, vaginally, intrauterinally or transdermally.

[0042] In detail, when administered transdermally, the composition is in gel or patch form.

[0043] It is specified that in the context of this disclosure, the term “hormone replacement component” is intended to refer to the administration of at least one of estrogen hormone, progestin hormone or selective modulator of estrogen hormone receptors.

[0044] In detail, this expression is to be meant with reference to a compound that has biological activity similar to progesterone, in the case of the progestin hormone, and similar to estrogen, in the case of the estrogen hormone.

[0045] In accordance with a first embodiment, the composition for use according to the present invention is used in the treatment of disorders associated with perimenopause and post-menopause selected from the group comprising: vasomotor syndrome, genitourinary syndrome, migrating muscle joint pain, sleep-wake rhythm changes, mood changes and sexual dysfunction.

[0046] In this case, the composition comprises one of:

[0047] 20 mg to 600 mg Elagolix or a pharmaceutically acceptable salt thereof;

[0048] 10 mg to 200 mg Relugolix or a pharmaceutically acceptable salt thereof;

[0049] 10 mg to 200 mg Linzagolix or a pharmaceutically acceptable salt thereof; in combination with one of a hormone replacement component selected from the following dosages:

[0050] 10 mcg to 5 mg Estradiol;

[0051] 10 mcg to 5 mg Estradiol hemi-hydrate;

[0052] 10 mcg to 5 mg Estradiol valerate;

[0053] 1 mg to 30 mg of Estetrol;

[0054] 10 mcg to 5 mg Estriol;

[0055] 0.1 mg to 2 mg equine conjugated estrogens;

[0056] 0.5 mg to 5 mg Dienogest;

[0057] 0.5 mg to 5 mg Drospirenone;

[0058] 5 mcg to 1 mg Levonorgestrel;

[0059] 1 mg to 10 mg Nomegestrol Acetate;

[0060] 0.1 mg to 10 mg Norethisterone acetate;

[0061] 0.1 mg to 10 mg Ciproterone acetate;

[0062] 10 mg to 500 mg Progesterone;

[0063] 1 mg to 20 mg Dydroge sterone;

[0064] 1 mg to 500 mg Medroxyprogesterone acetate;

[0065] 0.5 mg to 10 mg Tibolone;

[0066] 1 mg to 100 mg Bazedoxifene;

[0067] 1 mg to 100 mg Raloxifene.

[0068] In accordance with a second embodiment, the composition for use in accordance with the present invention is used in the treatment of immediate disorders associated with combined hormonal contraceptive treatment selected from the group comprising: abnormal uterine bleeding, spotting, headache, abdominal bloating, nausea, premenstrual syndrome.

[0069] In addition, the composition for use in accordance with the present invention is used in the treatment of immediate disorders associated with combined hormonal contraceptive treatment when administered in the treatment of dysmenorrhea, endometriosis and uterine fibromatosis.

[0070] The synergistic presence of the GnRH receptor antagonist in combination with estrogen hormone or progestin hormone or selective modulator of estrogen hormone receptors allows optimizing hormone therapy by taking advantage of the specific characteristics of the estro-progestins used, thus avoiding the side effects that arise in the first months of therapy and due to the overlap of exogenous hormones with endogenous ones, the latter being immediately inhibited by the concomitant administration of the GnRH receptor antagonist.

[0071] In this case, the composition comprises one of:

[0072] 20 mg and 600 mg Elagolix or a pharmaceutically acceptable salt thereof;

[0073] 10 mg and 200 mg Relugolix or a pharmaceutically acceptable salt thereof;

[0074] 10 mg and 200 mg Linzagolix or a pharmaceutically acceptable salt thereof; in combination with one of a hormone replacement component selected from the following dosages:

[0075] 5 to 100 mcg Ethinyl estradiol;

[0076] 10 mcg to 5 mg Estradiol;

[0077] 10 mcg to 5 mg Estradiol hemi-hydrate;

[0078] 10 mcg to 5 mg Estradiol valerate;

[0079] 1 mg to 30 mg Estetrol;

[0080] 1 mg to 5 mg Chlormadinone;

[0081] 10 mcg to 200 mcg Desogestrel;

[0082] 1 mg to 5 mg Dienogest;

[0083] 1 mg to 5 mg Drospirenone;

[0084] 0.1 mg to 20 mg Etonogestrel;

[0085] 10 mcg to 200 mcg Gestodene;

[0086] 10 mcg to 1 mg Levonorgestrel;

[0087] 10 mcg to 1 mg Nestorone (segesterone);

[0088] 1 mg to 10 mg Nomegestrol Acetate;

[0089] 1 mg to 20 mg Norelgestromin; 0.1 mg to 10 mg Norethisterone acetate;

[0090] 50 mcg to 500 mcg Norgestimate.

[0091] The synergistic presence of GnRH receptor antagonist, estrogen hormone and progestin hormone or selective modulator of estrogen hormone receptors ensures a zeroing of patients’ gonadal hormones and consequently a significant reduction in the immediate side effects of combined hormone therapy.

[0092] This allows HRT therapy to be employed significantly earlier than the onset of overt menopause, such as from the onset of the first menopausal symptoms, during perimenopause. This also significantly reduces the side effects of the first few months of treatment with combined hormonal contraceptives.

[0093] It has in practice been ascertained that the described invention achieves the intended objects.

[0094] EXAMPLE 1.

[0095] A pilot study conducted on women treated with Relugolix CT for uterine fibroids during the pre-menopausal years was carried out.

[0096] The planned duration of treatment was 12 weeks.

[0097] Data were collected from 11 pre-menopausal women.

[0098] The primary efficacy variable was the individual relative change in the average weekly number of moderate and severe hot flashes.

[0099] Weeks 5-12 of treatment were compared with the two weeks before the start of therapy.

[0100] Women aged 40-60 years, undergoing scheduled treatment for symptomatic fibroids with Relugolix CT and having at least 5 moderate or severe flushes per day, recorded during the 2-week pretreatment period, were considered.

[0101] The mean age of the women included was 48.6 years (range 46-57).

[0102] Moderate and severe flushes were reduced by 66.7% (p<0.05). The incidence of all types of flushes (mild+moderate+severe) was reduced by 70.8% (p<0.05). The VAS score of the most severe flushes decreased from 9.4 to 3.1 points (p<0.05).

[0103] Adherence to treatment at 12 weeks was 100%.

[0104] The most reported side effects during treatment were hair loss (2 / 11, 18.2%), abdominal bloating (2 / 11, 18.2%) and mood alterations (1 / 11, 9.1%). Therefore, treatment of fibroids with Relugolix CT resulted in a significant reduction in moderate and severe hot flashes (p<0.05) in symptomatic premenopausal women.

[0105] EXAMPLE 2.

[0106] The following is a study carried out to explore the potential synergistic benefit of the combination of Levonorgestrel intrauterine contraceptive 52 mg (LNG-IUS) and Relugolix CT in the treatment of uterine fibroids.

[0107] Uterine fibroids are the most common benign gynecologic tumors, with an incidence of up to 70% of women of reproductive age. Approximately 30% of these women have symptoms requiring clinical intervention. The most common manifestations comprise abnormal uterine bleeding (AUB), pelvic pain and compression-related symptoms.

[0108] Pharmacological management of fibroids remains complex, as none of the currently available therapies provide both long-term control of symptoms and stable reduction in fibroid volume. Many patients continue to have persistent symptoms or show poor response to treatment.

[0109] Hormonal therapies are the standard first-line approach. Among these, the 52-mg levonorgestrel-releasing intrauterine contraceptive system (LNG-IUS) is one of the most effective options.

[0110] By releasing levonorgestrel directly into the uterine cavity, it exerts local progestin effects leading to endometrial atrophy, reduced vascularization and significantly decreased menstrual bleeding.

[0111] For patients who do not adequately respond to local hormone therapy with progestin contraceptives, oral GnRH antagonists such as Relugolix combined therapy (Relugolix CT), which includes low doses of estradiol and norethisterone acetate, offer a systemic alternative. This treatment reduces the volume and vascularization of fibroids by inducing a controlled state of hypoestrogenism, without the marked suppression and side effects associated with GnRH agonists. This case series explores the potential synergistic benefit of combining LNG-IUS 52 mg and Relugolix CT in order to overcome the limitations of monotherapy and achieve more effective and lasting symptom control. Case 1:

[0112] A 46-year-old nulligravida woman with a history of two laparoscopic myomectomies was treated with Relugolix CT. Subsequently pelvic ultrasonography showed a 32x30 mm fundic fibroid and a 16x 18 mm lateral fibroid.

[0113] Endometrial thickness was 2 mm. Bone densitometry showed mild osteopenia (lumbar T-score -1.4). Treatment was continued without side effects.

[0114] Case 2:

[0115] A nulligravida woman with a history of endometrial and cervical polypectomies and previous hospitalization for menorrhagia received treatment with LNG-IUS and with Relugolix CT.

[0116] After starting the combination therapy, the bleeding resolved completely.

[0117] Ultrasound revealed a 9-mm intramural fibroid and diffuse adenomyosis. Endometrial thickness was 3 mm. No side effects were reported.

[0118] Case 3:

[0119] A 52-year-old woman, PARA 2002, with a marked family history of breast cancer and a previous endometrial biopsy negative for polyps, had persistent bleeding despite the use of LNG-IUS. After the start of Relugolix CT therapy, bleeding was resolved.

[0120] Ultrasound showed anterior and posterior fibroids (20x 15 mm and 33x 16 mm, respectively), associated with adenomyosis. Endometrial thickness was 2.6 mm. No adverse events occurred.

[0121] These cases demonstrate that the combination of LNG-IUS and Relugolix CT offers surprisingly better symptom control in women with symptomatic uterine fibroids, particularly when monotherapy is associated with side effects such as unpredictable bleeding.

[0122] The synergistic mechanism of action consists of local endometrial suppression exerted by LNG-IUS and systemic hormonal modulation induced by Relugolix CT.

[0123] In all three cases, patients reported a marked reduction in bleeding and improved quality of life, with no significant adverse events. Keeping the LNG-IUS in place during Relugolix CT therapy provides additional benefits.

[0124] In detail, local progestin action ensures persistent endometrial atrophy, thus minimizing the risk of bleeding both during and after systemic therapy. This is particularly important in preventing the rebound bleeding observed in some cases upon discontinuation of Relugolix alone. In addition, because LNG-IUS can remain in situ for several years, it provides prolonged endometrial stabilization well beyond the recommended duration for Relugolix CT therapy.

[0125] In addition, the use of Relugolix CT in perimenopausal women provides additional functional value through the alleviation of vasomotor symptoms, such as hot flashes, observed in two of the patients in this series.

[0126] The fact is emphasized that the special expedient of providing for the synergistic combination of at least one GnRH receptor antagonist with at least one of: an estrogenic hormone; a progestin hormone; a selective modulator of estrogen hormone receptors; allows immediate blocking of the patient’s endogenous hormonal fluctuations with the antagonist and provides an optimal estro-progestin combination that has no immediate side effects such as cycle disorders, headache, bloating and nausea allowing improved tolerance to the administration of such therapy.

Claims

CLAIMS1) Composition for use in the treatment of perimenopausal and post-menopausal symptomatology, comprising a combination of at least one GnRH receptor antagonist with at least one of: an estrogenic hormone; a progestin hormone a selective modulator of estrogen hormone receptors.2) Composition for use according to claim 1, characterized by the fact that saidGnRH receptor antagonist is selected from the list comprising: 4-[[(lR)-2-[5-(2- fluorine-3 -methoxyphenyl)-3 - [ [2-fluorine-6-(trifluoromethyl)phenyl]methyl] -4- methyl-2,6-dioxypyrimidin- 1-yl]- 1 -phenyl ethyl] amino]butanoic acid (Elagolix) or a pharmaceutically acceptable salt thereof, l-[4-[l-[(2, 6-difluorophenyl) methyl] -5 - [(dimethylamine) methyl] -3 -(6-methoxypyridazin-3 -yl)-2, 4- dioxytiene [2, 3-d ] pyrimidin-6-yl] phenyl] -3 -methoxyurea (Relugolix) or a pharmaceutically acceptable salt thereof, 5-carboxy-3-[2-fluorine-5-(2,3- difluorine-6-methoxybenzyloxy)-4-methoxyphenyl] thiene[3,4-d ] pyrimidine- 2,4 (1H, 3H)-dione (Linzagolix) or a pharmaceutically acceptable salt thereof3) Composition for use according to one or more of the preceding claims, characterized by the fact that said estrogen hormone is selected from the list comprising: (8R,9S,13S,14S,17R)-17-ethinyl-13-metyl-7,8,9,l l,12,14,15,16- octahydro-6H-cyclopenta[a]phenanthren-3,17-diol (Ethinyl-estradiol),(8R,9S, 13S, 14S, 17S)-13-metyl-6,7,8,9, 11, 12, 14, 15, 16, 17- decahydrocyclopenta[a]phenanthren-3,17-diol (Estradiol), Estra-l,3,5(10)-trien- 3,17b-diol hemihydrate (Estradiol hemihydrate), [(8R,9S,13S,14S,17S)-3- hydroxy-13-methyl-6,7,8,9,l l,12,14,15,16,17-deca- hydrocyclopenta[a]phenantren- 17-yl] pentanoate (Estradiol valerate), (8R,9S, 13S, 14S, 15R, 16R, 17R)-13- methyl-6,7,8,9, 11,12, 14, 15, 16, 17-deca- hydrocyclopenta[a]phenanthren-3,15, 16,17-tetrol (Estetrol),(8R,9S, 13S, 14S, 16R, 17R)- 13-methyl-6,7,8,9, 11,12, 14, 15, 16, 17- decahydrocyclopenta[a]phenanthren-3,16,17-triol (Estriol), Equine conjugated estrogens.4) Composition for use according to one or more of the preceding claims, characterized by the fact that said progestin hormone is selected from the list comprising: [(8R,9S, 10R, 13S, 14S, 17R)- 17-acetyl-6-chlorine-10, 13- dimethyl-3- oxy-2,8,9, 11, 12, 14, 15, 16-octahydron - 1H- cyclopenta[a]phenantren- 17-yl] acetate (Chlormadinone acetate), (8S,9S,10R,13S,14S,17R)-13-ethyl-17- ethynyl-1 l-methylen-1,2,3,6,7,8,9, 10, 12, 14, 15, 16- dodecahydrocyclopenta[a]phenanthren- 17-ol (Desogestrel), [( 170)- 17 -Hydroxy- 3-oxoestra-4,9-dien-17-yl]acetonitrile (Dienogest),(6R,7R,8R,9S, 10R, 13S, 14S, 15S, 16S, 17S)- 1,3', 4', 6, 6a, 7, 8, 9, 10, 11, 12, 13, 14, 15, 15a, 16- hexadecahydro- 10, 13- dimethylspiro- [17H-dicyclopropa-6,7: 15,16]cyclopenta [a]phenanthren 17,2'(5H)-furan]-3,5'(2H)-dione) (Drospirenone), (8S,9R,10S,13S,14S,17R)-13- Ethyl- 17-ethynyl- 17-hydroxy- 1 l-methylidene-2,6,7,8,9, 10, 12, 14, 15, 16- decahydro- lH-cyclopenta[a]phenantren-3-on (Etonogestrel),(8R,9S, 10R, 13S, 14S,17R)-13-Ethyl-17-ethynyl-17-hydroxy-1,2, 6, 7, 8, 9, 10, 11,12, 14-deca-hydrocyclopenta[a]phenantren-3-on (Gestodene), (-)-3 -ethyl- 17-ethynyl- 17-hydroxy- 1,2,6,7,8,9,10,11,12,13,14,15,16, 17- tetradecahydrocyclopenta phenanthren-3-on (Levonorgestrel),[(8R,9S,10R,13S,14S,17R)-17-acetyl-13-methyl-16-methylidene-3-oxo- 2,6,7,8,9,10,11,12,14,15 -decahydro- lH-cyclopenta[a]phenanthren- 17-yl] acetate (Nestorone), (6S,8R,9S,10R,13S,14S,17R)-17-acetyl-17-hydroxy- 6, 10, 13-trimethyl-2,6,7,8,9, 11,12, 14, 15, 16-decahydro-lH- cyclopenta[a]phenanthren-3-on (Medroxyprogesterone acetate), [(8S,9S, 10R, 13S, 14S, 17R)-17-acetyl-6, 13-dimethyl-3-oxo-1.2.8.9.10.11.12.14.15.16-decahydrocyclopenta [a]phenanthren- 17-yl] acetate(Nomegestrol Acetate), (8R,9S, 10R, 13S, 14S, 17R)- 13 -ethyl- 17-ethynyl- 17- hydroxy- 1,2, 6, 7, 8, 9, 10, 11, 12, 14-decahydrocyclopenta[a]phenantren-3-on (Norelgestromin), (8R,9S, 10R, 13S, 14S, 17R)- 17-ethynyl- 17-hydroxy- 13-metyl-1.2.6.7.8.9.10.11.12.14.15.16- dodecahydrocyclopenta[a]phenantren-3-on(Norethisterone acetate), (13-etil-17-ethynyl-3-hydroxymmino1,2,6,7,8,9,10,11,12,14,15,16- dodecahydrocyclopenta[a] phenanthren-17-yl)acetate (Norgestimate), 6-chlorine- lb,2b-dihydro- 17-hydroxy-3 'H- cyclopropa[l,2]pregna-l, 4, 6-triene-3, 20-dione 17-acetate (Cyproterone acetate), 4-Pregnene-3, 20-dione (Progesterone), 9b, 10a-pregna-4,6-dien-3, 20-dione (Dydrogesterone), (6S,8R,9S, 10R, 13S, 14S, 17R)-17-acetyl-17-hydroxy-6, 10, 13- trimetyl-2,6,7,8,9, 11, 12, 14, 15, 16-decahydro-lH-cyclopenta[a]phenantren-3-on (Medroxyprogesterone acetate).5) Composition for use according to one or more of the preceding claims, characterized by the fact that said selective modulator of estrogen hormone receptor is selected from the list comprising: (7R,8R,9S,13S,14S,17R)-17- ethynyl-17-hydroxy-7, 13-dimetyl-l,2,4,6,7,8,9, 11,12,14,15,16- dodecahydrocyclopenta[a]phenantren-3-on (Tibolone), l-[[4-[2-(azepan- 1- yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol (Bazedoxifene); [6-hydroxy-2-(4-hydroxyphenyl)-l-benzothiophen-3-yl]-[4-(2- piperidin- l-ilethoxy]phenyl]methanone (Raloxifene).6) Composition for use according to one or more of the preceding claims, characterized by the fact that the combination comprises separate dosages that are co-administered.7) Composition for use according to one or more of the preceding claims, characterized by the fact that the combination comprises at least one of:20 mg to 600 mg of said 4-[[(lR)-2-[5-(2-fluorine-3-methoxyphenyl)-3-[[2- fluorine-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxypyrimidin-l- yl]- 1 -phenylethyl] amino]butanoic acid (Elagolix) or a pharmaceutically acceptable salt thereof;10 mg to 200 mg of said l-[4-[l-[(2, 6-difluorophenyl) methyl]-5- [(dimethylamino) methyl] -3 -(6-methoxypyridazin-3-yl)-2, 4-dioxothieno [2, 3-d ] pyrimidin-6-yl] phenyl] -3 -methoxyurea (Relugolix) or a pharmaceutically acceptable salt thereof;10 mg to 200 mg of said 5-carboxy-3-[2-fluorine-5- (2,3-difluorine-6- methoxybenzyloxy)-4-methoxyphenyl] thieno[3,4-d] pyrimidine-2,4 (1H, 3H)-dione (Linzagolix) or a pharmaceutically acceptable salt thereof.8) Composition for use according to one or more of the preceding claims,characterized by the fact that said combination comprises at least one of:5 to 100 mcg of said (8R,9S,13S,14S,17R)-17-ethinyl-13-methyl- 7,8,9, 11,12, 14, 15, 16-octahydro-6H-cyclopenta[a]phenanthren-3, 17-diol (Ethinyl-e stradiol) ;10 mcg to 5 mg of said (8R,9S,13S,14S,17S)-13-methyl-6.7.8.9.11.12.14.15.16.17-deca-hydrocyclopenta[a]phenanthren-3, 17-diol (Estradiol);10 mcg to 5 mg of said Estra-l,3,5(10)-trien-3,17b-diol hemihydrate (Estradiol hemi-hydrate);10 mcg to 5 mg of said [(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6.7.8.9.11.12.14.15.16.17-deca-hydrocyclopenta[a]phenanthren-17- yl]pentanoate (Estradiol valerate);- 1 mg to 30 mg of said (8R,9S,13S,14S,15R,16R,17R)-13-methyl-6.7.8.9.11.12.14.15.16.17 -deca-hydrocyclopenta[a]phenanthren-3 ,15,16.17-tetrol (Estetrol);10 mcg to 5 mg of said (8R,9S,13S,14S,16R,17R)-13-methyl-6.7.8.9.11.12.14.15.16.17-deca-hydrocyclopenta[a]phenanthren-3, 16, 17- triol (Estriol);0.1 mg to 2 mg of said equine conjugated estrogens.9) Composition for use according to one or more of the preceding claims, characterized by the fact that said combination comprises at least one of:1 mg to 5 mg of said [(8R, 9S,10R,13S,14S, 17R)-17-acetyl-6-chlorine- 10,13- dimethyl-3-oxo-2,8,9, 11,12, 14, 15, 16-octahydro - 1H- cyclopenta[a]phenanthren- 17-yl] acetate (Chlormadinone acetate);10 mcg to 200 mcg of said (8S,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl- 11 -methylene- 1,2, 3, 6, 7, 8, 9, 10, 12, 14, 15, 16- dodecahydrocyclopenta[a]phenanthren- 17-ol (Desogestrel);0.5 mg to 5 mg of said [(170)-17-Hydroxy-3-oxoestra-4,9-dien-17- yl] acetonitrile (Dienogest);- 0.5 mg to 5 mg of said (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3', 4', 6, 6a, 7, 8, 9, 10, 11, 12, 13, 14, 15, 15a, 16- hexadecahydro- 10, 13-dimethylspiro- [17H-dicyclopropa-6,7: 15,16]cyclopenta [a]phenanthren- 17,2'(5H)-furan]-3,5'(2H)-dione) (Drospirenone);- 0.1 mg to 20 mg of said (8S,9R,10S,13S,14S,17R)-13-Ethyl-17-ethynyl-17- hydroxy-l l-methylidene-2,6,7,8,9,10,12,14,15,16-decahydro-lH- cyclopenta[a]phenanthren-3-on (Etonogestrel);10 mcg to 200 mcg of said (8R,9S,10R,13S,14S,17R)-13-Ethyl-17-ethynyl- 17-hydroxy- 1,2, 6, 7, 8, 9, 10, 11,12, 14-decahydrocyclopenta[a]phenanthren-3- on (Gestodene);10 mcg to 1 mg of said (-)-3-ethyl-17-ethynyl-17-hydroxy- 1,2,6,7,8,9,10,11,12,13,14,15,16, 17- tetradecahydrocyclopenta phenanthren-3-on (Levonorgestrel);10 mcg to 1 mg of said [(8R,9S,10R,13S,14S,17R)-17-acetyl-13-methyl-16- methylidene-3-oxo-2,6,7,8,9, 10,11,12,14,15 -decahydro- 1H- cyclopenta[a]phenanthren- 17-yl] acetate (Nestorone);1 mg to 500 mg of said (6S,8R,9S,10R,13S,14S,17R)-17-acetyl-17-hydroxy- 6, 10, 13-trimethyl-2,6,7,8,9, 11,12, 14, 15, 16-decahydro-lH- cyclopenta[a]phenanthren-3-on (Medroxyprogesterone acetate);1 mg to 10 mg of said [(8S,9S,10R,13S,14S,17R)-17-acetyl-6,13-dimethyl- 3-oxo- 1,2, 8, 9, 10, 11, 12, 14, 15, 16-decahydrocyclopenta [a]phenanthren- 17- yl] acetate (Nomegestrol Acetate);- 1 to 20 mg of said (8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-17- hydroxy-1,2,6,7,8,9, 10, 11,12, 14-decahydrocyclopenta[a]phenanthren-3-on (N orelgestromin) ;0.1 mg to 10 mg of said (8R,9S,10R,13S,14S,17R)-17-ethynyl-17-hydroxy- 13-methyl-l,2,6,7,8,9, 10, 11,12, 14, 15, 16- dodecahydrocyclopenta[a]phenanthren-3-on (Norethisterone acetate);50 mcg to 500 mcg of said (13 -ethyl- 17-ethynyl-3 -hydroxyimino 1,2, 6, 7, 8, 9, 10, 11,12, 14, 15,16- dodecahydrocyclopenta[a] phenanthren- 17- yl) acetate (Norgestimate);0.1 mg to 10 mg of said 6-chlorine-lb,2b-dihydro-17-hydroxy-3'H- cyclopropa[ l,2]pregna- 1,4, 6-triene-3, 20-dione 17-acetate (Cyproteroneacetate);10 mg to 500 mg of said 4-Pregnene-3, 20-dione (Progesterone);1 mg to 20 mg of said 9b, 10a-pregna-4,6-dien-3, 20-dione (Dydrogesterone);1 mg to 500 mg of said (6S,8R,9S,10R,13S,14S,17R)-17-acetyl-17-hydroxy-6.10.13-trimethyl-2,6,7,8,9, 11,12, 14, 15, 16-decahydro-lH- cyclopenta[a]phenanthren-3-on (Medroxyprogesterone acetate).10) Composition for use according to one or more of the preceding claims, characterized by the fact that said combination comprises at least one of:0.5 mg to 10 mg of said (7R,8R,9S,13S,14S,17R)-17-ethynyl-17-hydroxy-7.13-dimethyl- 1,2, 4, 6, 7, 8, 9, 11,12, 14, 15,16- dodecahydrocyclopenta[a]phenanthren-3-on (Tibolone);1 mg to 100 mg l-[[4-[2-(azepan-l-yl)ethoxy]phenyl]methyl]-2-(4- hydroxyphenyl)- mg of said 3-methylindol-5-ol (Bazedoxifene);1 mg to 100 mg of [6-hydroxy-2-(4-hydroxyphenyl)-l-benzothiophen-3-yl]- [4-(2-piperidin- l-ilethoxy)phenyl] methanone (Raloxifene).11) Composition for use according to one or more of the preceding claims, characterized by the fact that the composition is for use in the treatment of disorders associated with perimenopause and post-menopause selected from the group comprising: vasomotor syndrome, genitourinary syndrome, migrating muscle joint pain, sleep-wake rhythm changes, mood changes and sexual dysfunction.12) Composition for use according to one or more of the preceding claims, characterized by the fact that the composition is for use in the treatment of disorders associated with combined hormonal contraceptive treatment selected from the group comprising: menstrual irregularities, headache, nausea and abdominal bloating.13) Composition for use according to one or more of the preceding claims, characterized by the fact that the composition is administered orally, vaginally, intrauterinelly or trans-dermally.