Patent Document

This application is a continuation-in-part of U.S. Ser. No. 10/753,073, filed Jan. 8, 2004, now abandoned, which was a continuation-in-part of (i) U.S. Ser. No. 09/284,147, filed Mar. 17, 1999, now U.S. Pat. No. 6,831,073, issued Dec. 14, 2004, §371 national stage of PCT International Application No. PCT/FR97/01792, filed Oct. 8, 1997, claiming priority of French Patent Application No. 96/12239, filed Oct. 8, 1996; and (ii) U.S. Ser. No. 09/423,108, filed Oct. 29, 1999, now U.S. Pat. No. 6,906,049, issued Jun. 14, 2005, claiming priority of PCT International Application No. PCT/FR99/02587, filed Oct. 25, 1999. 
    
    
     BRIEF SUMMARY OF THE INVENTION 
     The present invention relates to the field of therapeutic chemistry and more particularly to the field of hormonal pharmaceutical techniques. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     A more precise subject of the invention is new pharmaceutical compositions formed by an estroprogestative combination with a view to the correction of estrogenic deficiencies in natural or artificial menopauses or in order to stop ovulation of women during their period of ovarian activity. 
     In particular a subject of the invention is an estroprogestative combination, characterized in that it is constituted by unit doses containing the combination of a progestative and an estrogen, the two components being present simultaneously in each medicinal dose. 
     This combination is intended to be administered by oral route. 
     As is known, the life expectancy of women has passed in less than a century from 50 to 80 years, whilst the average age for the onset of the menopause has remained unchanged. Therefore, women spend a third of their life in a state of estrogenic deficiency which is the origin of the increase in risk of osteoporosis and cardiovascular illnesses. 
     Sequential replacement treatment for the menopause cures the climateric symptomology a id prevents osteoporosis and the onset of illnesses. It creates artificial cycles which are followed by a withdrawal bleeding. This therapeutic schema quite particularly suits women for whom the menopause is recent but it is not always well accepted in the long term, which in part explains the poorer observance of treatment (DRAPIER FAURE E.; Gynecologie. 1992, 43: 271-280). 
     In order to overcome this drawback, combined combinations have been perfected where the two components are taken simultaneously, the progestative having the effect of permanently opposing the proliferative action of the estrogen on the endometrium, by creating an atrophy of the endometrium and as a consequence, the absence of withdrawal bleeding (HARGROVE J. T., MAXSON W. S., WENTZ A. C., BURNETT L. S., Obstet Gynecol, 1989, 73: 606-612). 
     This “no periods” schema more particularly suits women for whom the menopause is already well in the past. It can be prescribed in courses of sequential combinations in order to improve the long-term observance of replacement hormone treatment for the menopause. 
     The dose of progestative to be used in a combined replacement treatment is in general deduced from that which is usually prescribed in sequential schemata. In the latter the dose chosen is that which gives over the long term less than 1% endometrial hyperplasia when the progestative is administered discontinuously, more than 10 days per cycle, in post-menopausal women under replacement estrogenotherapy (WHITEHEAD et al., J. reprod. Med, 1982, 27: 539-548, PATERSON et al, Br Med J, Mar. 22, 1980, 822-824). 
     In the combined treatment, these same progestatives were used at half the dose judged to be effective during a sequential treatment: this is the example of the micronized progesterone, didrogesterone (FOX H., BAAK J., VAN DE WEDER P., AL-AZZAWI E., PATERSON M., JOHNSON A., MICHELL G., BARLOW D., FRANCIS R., 7th International Congress on the Menopause, Stockholm, Jun. 20-24, 1993, abstr 119) and medroxyprogesterone acetate (BOCANERA R, BEN J., COFONE M., GUINLE I., MAILAND D., SOSA M., POUDES G., ROBERTI A., BISO T., EZPELETA D., PUCHE R., TOZZINI R., 7th International Congress on the Menopause, Stockholm, Jun. 20-24, 1993, abstr 40) which were used at doses of 100, 10 and 5 mg/day respectively, with encouraging results on the clinical and endometrial level. 
     Among the progestatives, nomegestrol acetate appeared to be one of the most effective. Nomegestrol acetate is a non-androgenic progestative derived from 19-nor progesterone, its use in sequential administration during the menopause at the dose of 5 mg/day, 12 days per cycle, in combination with different types of estrogens, allows endometrial hyperplasia to be prevented as shown by a multicentre study on 150 women for one year (THOMAS J. L., BERNARD A. M., DENIS C., 7th International Congress on the Menopause, Stockholm, Jun. 20-24, 1993, abstr 372). 
     The absence of hyperplasia was confirmed in a study where the nomegestrol acetate was administered at the same dose, 14 days per cycle, in women treated with percutaneous estradiol (BERNARD A. M. et al. Comparative evaluation of two percutaneous estradiol gels in combination with nomegestrol acetate in hormone replacement therapy. XIV World Congress of Gynecology and Obstetrics, FIGO, Montreal, Sep. 24-30, 1994). 
     The combined treatment is more often used in a continuous fashion, i.e. without interruption. However some people are in favour of using it in an intermittent fashion, for example 25 days per month (BLRKAUSER M. ET AL; Substitution hormonale: une indication bien posée et des schémas de traitement individuels sont déterminants pour le succès du traitement, Méd. et Hyg., 1995, 53: 1770-1773). The aim of the therapeutic interruption is to remove the inhibition exercised by the progestative on the synthesis of the estradiol and progesterone receptors and in this way to avoid the lowering of receptivity of the hormono-dependant tissues. 
     The progesterone used according to the present invention is nomegestrol acetate which is active by oral route. 
     The estrogen used is free or esterified estradiol, or conjugated equine estrogens which are presented according to a formulation which is active by oral route and in particular estradiol valerate. 
     Nomegestrol acetate and free or esterified estradiol or conjugated equine estrogens are administered in one of the forms which permit administration by oral route: gelatine capsules, capsules, pills, sachets of powder, tablets, coated tablets, sugar-coated tablets etc. 
     The present invention is characterized in that it is constituted by a new estroprogestative combination, which is active by oral route and administered in a combined manner. A subject of the present invention is also its use in the correction of estrogenic deficiencies, in the prevention of osteoporosis and cardiovascular illnesses in post-menopausal women, or in stopping ovulation in women during their period of ovarian activity. 
     The compositions according to the invention based on nomegestrol and free or esterified or equine conjugated estrogens are administered in a continuous fashion or intermittent fashion from 21 to 25 days per month. 
     According to a particular implementation of the invention the compositions contain a quantity of nomegestrol acetate ranging from 1.5 to 3.75 mg and a quantity of free or esterified estradiol or conjugated equine estrogens ranging from 0.5 to 3 mg. Preferably, the optimal formulations contain 2.5 mg of nomegestrol acetate combined with: either 1.5 mg of free estradiol or 2 mg of estradiol ester or 0.625 mg of conjugated equine estrogens, per daily dose. 
     This combined administration method can have several therapeutic indications. In post-menopausal women, the estroprogestative combination is intended to compensate for the functional disorders brought about by hypoestrogenism of the menopause, while maintaining an atrophy of the endometrium and avoiding in a majority of them the appearance of withdrawal bleeding. 
     In women during the period of ovarian activity, young or in the years preceding the menopause, the cyclic administration of the hormonal combination is capable of stopping ovulation and of exercising a contraceptive effect insofar as it has been proved that nomegestrol is capable of stopping the ovulation peak of LH and FSH, starting from 1.25 mg/day (BAZIN B. et al, Effect of nomegestrol acetate, a new 19-norprogesterone derivative on pituitary ovarian function in women. Br. 1. Obstet. Gynaecol., 1987, 94: 1199-1204). When the hormonal combination is given for a contraceptive purpose, the aim of nomegestrol acetate is to stop ovulation and for the estrogenic compound to compensate for hypoestrogenia and ensure a better control of the cycle. 
     A subject of the present invention is also a process for obtaining new pharmaceutical compositions. 
     The obtaining process according to the invention consists of mixing the active ingredients: nomegestrol acetate and free or esterified estradiol or conjugated equine estrogens with one or more pharmaceutically acceptable, non-toxic, inert excipients. 
     Among the excipients which can be mentioned are binding and solubilizing agents, compression agents, disintegration agents and slip agents. 
     This mixture can be subjected to direct compression or to several stages of compression in order to form tablets which, if desired, can have their surface protected by a film, by lacquering or coating. The production of tablets by direct compression allows a maximum reduction in the proportion of diluting agents, binding agents, disintegration agents and slip agents. 
     The production of gelatine capsules can be carried out by mixing the active ingredients with an inert diluent and a slip agent. 
     The tablets contain, in particular, mass diluting agents such as lactose, sorbitol for direct compression, marketed under the name NEOSORB 60, Palatinite which is a registered trademark for designating an equimolar mixture of the isomer of -D-glucopyranosido 1,6-mannitol and -D-glucopyranosido 1,6-glucitol crystallized with two molecules of water, mannitol, sorbitol or the mixture lactose/PVP sold under the name Ludipress. 
     The compression binding agents are in general microcrystalline celluloses such as those sold under the name AVICEL PH 101 or AVICEL PH 102. 
     The polyvinylpyrrolidone plays an important role and facilitates the agglomeration of the powders and the compressibility of the mass. To this end polyvinylpyrrolidones are used with a molecular weight comprised between 10000 and 30000 such as Povidone, Kollidon of a grade comprised between 12 and 30. 
     The mixture also contains slip or anti-electrostatic agents so that the powder does not agglomerate in the feed hoppers. In this respect, colloidal silicas can be mentioned which are sold under the name AEROSIL 100 or AEROSIL 200. 
     The mixture also contains disintegration agents which allow disintegration or crumbling which conforms to pharmaceutical standards. There can be mentioned as useful disintegration agents, polymers of cross-linked vinylpyrrolidones such as those sold under the names Polyplasdone or Polyclar AT, carboxymethylamidons such as those sold under the names Amigel or Explotab, cross-linked carboxymethylcelluloses or croscarmelloses such as the compound sold under the name AC-DI-SOL&gt;. 
     In addition, the preparation contains lubrication agents which facilitate the compression and ejection of the tablet from the tablet compressing machine. There can be mentioned as lubrication agents, glycerol palmitostearate sold under the name Precirol, magnesium stearate, stearic acid or talc. 
     After compression the tablets can be coated in order to ensure their storage or to facilitate their deglutination. 
     The coating agents are either of cellulose origin such as cellulose phthalate (Sepifilm, Pharmacoat), or of polyvinyl origin of Sepifilm ECL type, or of saccharose origin such as the sugar for sugar-coating of Sepisperse DR, AS, AP OR K (coloured) type. 
     The tablets, whether coated or not, can in addition, be surface or bulk coloured, by plant or synthetic colouring agents (for example chinolin yellow lacquer or E 104). 
     The proportions of the different constituents vary according to the type of tablet to be produced. 
     The content of active ingredients can vary from 1.5 to 3.75 mg for nomegestrol acetate and from 0.5 to 3 mg for free or esterified estradiol or for conjugated equine estrogens. The dilution agents vary from 20 to 75% of the total mass, the slip agents from 0.1 to 2% of the total mass, the compression binding agents vary from 2 to 20%, the polyvinylpyrrolidone from 0.5 to 15%, the disintegration agents vary from 2 to 5.5% for the cross-linked polyvinylpyrrolidone or the carboxymethylamidon, from 2.0 to 3.0% for the croscarmellose. 
     The quantities of lubricating agents vary as function of the type of agents from 0.1 to 3.0%. 
     The compositions according to the invention are intended to be administered once per day. However, depending on the therapeutic requirements, administration can be split up (twice per day) or on the other hand, repeated (two tablets per day). The following examples illustrate the invention. They in no way limit it. 
     Example I 
     Tablets with 4 mg of Active Ingredient 
                                                                           Active ingredients:   estradiol   1.5   mg               nomegestrol acetate   2.5   mg                Microcrystalline cellulose   22.4   mg           (marketed under the name AVICEL PH 102)           Lactose   60   mg           Polyvinylpyrrolidone   8.4   mg           Colloidal silica   1.2   mg           Glycerol palmitostearate   3.6   mg           Colouring agent E.104   0.4   mg                        
for a tablet completed at an average weight of 100 mg.
 
     Example II 
     Study of the Clinical Tolerance During Two Continuous Combined Schemata of Hormone Replacement Therapy for the Menopause 
     The pilot study is carried out over 24 weeks on two parallel groups subjected to treatments A and C: 
     Treatment A 
     
         
         
           
             Nomegestrol acetate 2.5 mg/day every day+percutaneous 17β-estradiol 1.5 mg/day every day. 
             The nomegestrol acetate is administered in the form of tablets and the percutaneous 17β-estradiol in the form of a gel.
 
Treatment C
 
             Nomegestrol acetate 2.5 mg/day every day+estradiol valerate 2 mg/day every day. 
             The estradiol valerate is administered in the form of tablets. 
           
         
       
    
     The pilot study is intended to evaluate the endometrial clinical tolerance during the use of the two hormone replacement therapy schemata for the menopause so called “without periods” combining in a continuous combined fashion treatment A or C. The endometrial clinical tolerance is evaluated from the presence or not of occurrences of vagina bleeding, their intensity, their frequency, from data acquired from endovaginal echographical examination etc. 
     Also, another aim of this study is to assess the general clinical tolerance (weight, blood pressure, mammary symptoms), biological tolerance (Formule Numeration Sanguine (blood count), glycemia, cholesterol . . . ), as well as the observance of treatment. 
     The selection of subjects is carried out as a function of “inclusion” criteria. These criteria are to do:
         with the menopause:
 
women over 50 years old are included who have had a natural menopause expressed clinically by an amenorrhea greater than 12 months and less than 10 years, the women having had a natural menopause confirmed biologically by quantitative analysis of FSH (Follicle stimulating hormone) and estradiol (i.e. plasmatic FSH≧20 IU/I, plasmatic E 2 ≦0.11 nmol/l).
   with women:
 
women who have not had hysterectomies are included, whose Quetelet&#39;s index (weight in kg/(height in m) 2 ) is ≦27, having had regular cycles before the menopause, having never received hormone replacement therapy for the menopause or having had a clinically well tolerated hormone replacement therapy (absence of abnormal bleeding), interrupted for more than 6 weeks, presenting an endometrial thickness measured by endovaginal echography ≦5 mm, accepting the idea of hormone replacement therapy for the menopause, who would like a hormone therapy without periods, justifying an estroprogestative hormone therapy for at least 6 months, cooperative: accepting to conform to the requirements of the study, whose psychic and intellectual profile would allow one to suppose a good observance of the treatment, having a mammograph dating from less than a year from the date of inclusion.
       

     At the start of treatment the patients undergo an inclusion consultation (C 1 ) the purpose of which is to verify that the inclusion criteria have been respected, that the endovaginal echograph is normal and to obtain the written consent of the patient as regards participation. 
     The intermediate consultation (C 2 ) takes place between the 9th and 11th week of treatment, the purpose of which is to verify mammary and endometrial clinical tolerance is good as regards the treatment. 
     Lastly, a final consultation (C 3 ) takes place during the 24th week of treatment. 
     The patients who wish to continue the study can receive, for 24 additional weeks, the estroprogestative treatment received during the study according to the same therapeutic schema. The extension of the study thus allows a complete monitoring of the study over 48 weeks. 
     Analysis of the Study 
     Results I 
     The attached Tables I and II, reveal a difference in terms of the amenorrhea results (i.e. no bleeding from 0 to 24 weeks) and of mammary and/or endometrial tolerance as a function of the estrogen. 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE I 
               
             
             
               
                   
               
               
                 Treatment A 
               
               
                 Nomegestrol acetate + percutaneous 17β-estradiol 
               
             
          
           
               
                 Elapse since 
                   
                   
                 Duration of 
                 Endometrial 
                   
               
               
                 menopause 
                 Presence of HRT 
                 Start of 
                 treatment 
                 thickness 
               
               
                 ameno/month 
                 previously 
                 treatment 
                 weeks 
                 before/after mm 
                 COMMENTS 
               
               
                   
               
             
          
           
               
                 72 
                 no 
                 17 Oct. 1994 
                 24 
                 2/2 
                 Amenorrhea 
               
               
                   
                   
                   
                 24 ext 
                   
                 endometrial thickness after 48 weeks of treatment = 2 mm 
               
               
                 82 
                 no 
                 04 Nov. 1994 
                 24 
                 3/3 
                 amenorrhea 
               
               
                   
                   
                   
                 extension 
               
               
                 26 
                 yes 
                 09 Jan. 1995 
                 24 
                 3/3 
                 amenorrhea 
               
               
                   
                 well tolerated 
                   
                 extension 
               
               
                 108 
                 no 
                 16 Jan. 1995 
                 24 
                 1/4 
                 amenorrhea 
               
               
                   
                   
                   
                 extension 
               
               
                 48 
                 no 
                 13 Feb. 1995 
                 24 
                 3/2 
                 1 episode of bleeding at 42 days (a few drops) between 
               
               
                   
                   
                   
                   
                   
                 the 1 st  and 6 th  weeks; breast tension and pain of 
               
               
                   
                   
                   
                   
                   
                 minimal intensity from the 1st to the 22nd week (7 
               
               
                   
                   
                   
                   
                   
                 days/week) 
               
               
                   
                   
                   
                   
                   
                 Extension not effected: did not pick up the treatment 
               
               
                   
                   
                   
                   
                   
                 kit owing to holidays; following the same treatment 
               
               
                   
                   
                   
                   
                   
                 outside protocol 
               
               
                 24 
                 no 
                 10 Mar. 1995 
                 24 
                 2/5 
                 Amenorrhea; breast tension and pain of slight intensity 
               
               
                   
                   
                   
                 extension 
                   
                 from the 6th to the 12th week (7 days/week) 
               
               
                 55 
                 yes 
                 20 Mar. 1995 
                 24 
                 4/8 
                 amenorrhea 
               
               
                   
                 well tolerated 
                   
                 extension 
               
               
                 27 
                 yes 
                 08 May 1995 
                 24 
                 3/5 
                 Amenorrhea 
               
               
                   
                 well tolerated 
                   
                   
                   
                 Extension not effected: did not pick up the treatment 
               
               
                   
                   
                   
                   
                   
                 kit owing to holidays; same treatment outside protocol 
               
               
                 90 
                 yes 
                 10 Apr. 1995 
                 24 
                 4/4 
                 amenorrhea 
               
               
                   
                 well tolerated 
                   
                 extension 
               
               
                 13 
                 yes 
                 03 Jul. 1995 
                 24 
                 1 pending 
                 amenorrhea 
               
               
                   
                 well tolerated 
                   
                 extension 
               
               
                 99 
                 yes 
                 24 Apr. 1995 
                 24 
                 1/4 
                 amenorrhea 
               
               
                   
                 well tolerated 
                   
                 extension 
               
               
                 21 
                 yes 
                 26 Jun. 1995 
                 24 
                 4 pending 
                 amenorrhea 
               
               
                   
                 well tolerated 
                   
                 extension 
               
               
                 96 
                 ? 
                 29 May 1995 
                 24 
                 2 pending 
                 amenorrhea 
               
               
                   
                   
                   
                 extension 
               
               
                 65 
                 yes 
                 10 May 1995 
                 24 
                 1/3 
                 amenorrhea; 10 episodes (4 days/week) of breast pains 
               
               
                   
                 well tolerated 
                   
                 extension 
                   
                 of minimal intensity 
               
               
                 13 
                 no 
                 12 Jun. 1995 
                 Stopped at 6 
                 3 not measured 
                 continuous slight bleeding from the 5th week until 
               
               
                   
                   
                   
                   
                   
                 treatment stopped 
               
               
                 38 
                 yes 
                 10 Jul. 1995 
                 24 
                 2 pending 
                 amenorrhea 
               
               
                   
                 well tolerated 
                   
                 extension 
               
               
                   
               
               
                 EXTENSION = 24 additional weeks of treatment 
               
               
                 HRT = hormone replacement therapy 
               
             
          
         
       
     
     Conclusion 
     Of the 16 patients treated:
         1 left the study, i.e. 6%   15 finished the study after 24 weeks, i.e. 94%   13 extensions of treatment (24 additional weeks) 81%
 
The two extensions which did not take place when due to reasons which were independent of the treatment, the patients continued the same treatment outside the treatment protocol.
       

     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE II 
               
             
             
               
                   
               
               
                 Treatment C 
               
               
                 Nomegestrol acetate + estradiol valerate per os 
               
             
          
           
               
                 Elapse since 
                   
                   
                 Duration of 
                 Endometrial 
                   
               
               
                 menopause 
                 Presence of HRT 
                 Start of 
                 Treatment 
                 Thickness 
               
               
                 ameno/month 
                 previously 
                 treatment 
                 weeks 
                 before/after mm 
                 COMMENTS 
               
               
                   
               
             
          
           
               
                 72 
                 no 
                 21 Nov. 1994 
                 stopped at 8 
                 4/* 
                 amenorrhea, breast tension and pain of slight intensity 
               
               
                   
                   
                   
                   
                   
                 from the 2nd week to the 8th week; STOPPED owing to 
               
               
                   
                   
                   
                   
                   
                 high abdominopelvic tension due to increased size of a 
               
               
                   
                   
                   
                   
                   
                 sub-serous fibroma: echo before treatment = 37 mm; echo 
               
               
                   
                   
                   
                   
                   
                 after 8 weeks of treatment = 75 mm 
               
               
                 46 
                 yes 
                 28 Nov. 1994 
                 24 
                 3/6 
                 1 episode of bleeding of 31 days between the 5 th  and 
               
               
                   
                 well tolerated 
                   
                 extension 
                   
                 the 9 th  week (a few drops) 
               
               
                 31 
                 yes 
                 28 Nov. 1994 
                 stopped at 10 
                 2 not measured 
                 amenorrhea, STOPPED for insomnia, nervousness and pain 
               
               
                   
                 well tolerated 
                   
                   
                   
                 in lower limbs 
               
               
                 60 
                 yes 
                 30 Jan. 1995 
                 24 
                 4/2 
                 amenorrhea, breast tension and pain of slight intensity 
               
               
                   
                 well tolerated 
                   
                 extension 
                   
                 from 2 nd  week of treatment until the 19 th  week 
               
               
                 121 
                 yes 
                 06 Feb. 1995 
                 stopped at 9 
                 3 not measured 
                 1 episode of bleeding of 16 days of low intensity from 
               
               
                   
                 well tolerated 
                   
                   
                   
                 the 6th week; breast tension of minimal intensity from 
               
               
                   
                   
                   
                   
                   
                 the 2nd week to the 8 th  week; STOPPED owing to 
               
               
                   
                   
                   
                   
                   
                 headaches, night sweats and a blood pressure of 17/10 
               
               
                 36 
                 yes 
                 06 Feb. 1995 
                 24 
                 4* 
                 amenorrhea, 23 episodes of breast tension of high 
               
               
                   
                 well tolerated 
                   
                   
                   
                 intensity of 7 days/week; extension impossible as 
               
               
                   
                   
                   
                   
                   
                 estrogen dose reduced due to breast tension 
               
               
                 47 
                 yes 
                 27 Feb. 1995 
                 24 
                 2/2 
                 amenorrhea; 6 episodes of breast tension and pain of 
               
               
                   
                 well tolerated 
                   
                 extension 
                   
                 slight intensity (2 days/week) 
               
               
                 62 
                 no 
                 13 Mar. 1995 
                 24 
                 1/4 
                 amenorrhea 
               
               
                   
                   
                   
                 extension 
               
               
                 74 
                 yes 
                 20 Mar. 1995 
                 24 
                 4/6 
                 amenorrhea 
               
               
                   
                 well tolerated 
                   
                 extension 
               
               
                 110 
                 yes 
                 08 May 1995 
                 stopped at 18 
                 2 not measured 
                 amenorrhea until 12 weeks then 1 episode of bleeding 
               
               
                   
                 well tolerated 
                   
                   
                   
                 of 41 days until treatment stopped 
               
               
                 16 
                 yes 
                 22 May 1995 
                 24 
                 1 pending 
                 amenorrhea 
               
               
                   
                 well tolerated 
                   
                 extension 
               
               
                 60 
                 yes 
                 12 Jun. 1995 
                 stopped at 16 
                 2/3 
                 4 episodes of bleeding of low intensity (6 days/week) 
               
               
                   
                 well tolerated 
                   
                   
                   
                 5 episodes of breast pain of medium intensity (6 days/ 
               
               
                   
                   
                   
                   
                   
                 week); STOPPED owing to mastitis and a breast abscess 
               
               
                 11 
                 no 
                 19 Jun. 1995 
                 24 
                 2 pending 
                 1 episode of bleeding 12 days (a few drops) 
               
               
                   
                   
                   
                 extension 
               
               
                 38 
                 yes 
                 03 Jul. 1995 
                 stopped at 4 
                 5 not measured 
                 1 episode of bleeding of 11 days until treatment 
               
               
                   
                 well tolerated 
                   
                   
                   
                 stopped of low intensity 
               
               
                   
               
               
                 *= not measured at the control echo 
               
             
          
         
       
     
     Conclusion 
     Of the 14 patients treated
         6 left the study i.e. 43%   8 finished the study after 24 weeks, i.e. 57%   7 extensions of treatment (24 additional weeks), i.e. 50%
 
% of amenorrhea (i.e. no occurrence of bleeding for 24 weeks)=43%
 
Results II
 
A—Observance
       

     While no significant difference exists between the two groups A and C, a lower number of days when treatment lapsed over all the 24 weeks of the study was observed with treatment A. 
     B—Endometrial Clinical Tolerance 
     The most significant absolute percentage of amenorrhea is found in group A, the difference being significant in phase II (13th to 24th week of treatment) As has been described in the literature, the percentage of amenorrhea increases with time; therefore, for group C, it is 35.3% during the first 12 weeks of treatment, and 46.1% during the last 12 weeks. 
     The attached tables III, IV and V illustrate the results obtained. 
     Amenorrhea 
     Analysis Regarding Treatment 
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE III 
               
               
                   
               
               
                 Phase I/weeks 1 to 12 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                   
                 TOTAL 
                   
                 GROUP A 
                   
                 GROUP C 
                   
               
             
          
           
               
                   
                 N 
                 % 
                 N 
                 % 
                 N 
                 % 
                 P 
               
               
                   
               
               
                 Amenorrhea 
                   
                   
                   
                   
                   
               
               
                 yes 
                 19 
                 37.2% 
                 9 
                 50% 
                 6 
                 35.3% 
               
               
                 no 
                 32 
                 62.7% 
                 9 
                 50% 
                 11 
                 64.7% 
                 0.316 
               
               
                 Spotting 
               
               
                 yes 
                 32 
                 62.7% 
                 9 
                 50% 
                 11 
                 64.7% 
               
               
                 no 
                 19 
                 37.2% 
                 9 
                 50% 
                 6 
                 35.3% 
                 0.316 
               
               
                   
               
             
          
           
               
                   
                 TOTAL 
                 GROUP A 
                 GROUP C 
                   
               
             
          
           
               
                   
                   
                 avg ± week 
                   
                 avg ± week 
                   
                 avg ± week 
                   
               
               
                   
                 N 
                 (min:max) 
                 N 
                 (min:max) 
                 N 
                 (min:max) 
                 P 
               
               
                   
               
               
                 Total duration of bleeding 
                 51 
                 9.1 ± 2.1 
                 18 
                 9.1 ± 4.5 
                 17 
                 8.9 ± 2.7 
                 0.412 
               
               
                 (days) 
                   
                  0:70 
                   
                  0:70 
                   
                  0:31 
               
               
                 Average intensity 
                 51 
                 0.8 ± 0.1 
                 18 
                 0.7 ± 0.2 
                 17 
                 0.9 ± 0.2 
                 0.446 
               
               
                   
                   
                 0:2 
                   
                 0:2 
                   
                   0:2.5 
               
               
                 Number of weeks of 
                 51 
                 2.1 ± 0.4 
                 18 
                 1.8 ± 0.7 
                 17 
                 2.1 ± 0.5 
                 0.552 
               
               
                 bleeding 
                   
                  0:10 
                   
                  0:10 
                   
                 0:7 
               
               
                 Total number of episodes 
                 51 
                 1.2 ± 0.2 
                 18 
                   1 ± 0.3 
                 17 
                 1.2 ± 0.4 
                 0.434 
               
               
                   
                   
                 0:6 
                   
                 0:4 
                   
                 0:6 
               
               
                   
               
               
                 None of the patients suffered from metrorrhagias during phase I 
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE IV 
               
               
                   
               
               
                 Phase II/weeks 13 to 24 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                   
                 TOTAL 
                   
                 GROUP A 
                   
                 GROUP C 
                   
               
             
          
           
               
                   
                 N 
                 % 
                 N 
                 % 
                 N 
                 % 
                 P 
               
               
                   
               
               
                 Amenorrhea 
                   
                   
                   
               
               
                 yes 
                 20 
                 42.5% 
                 12 
                 66.7% 
                 6 
                 46.1% 
               
               
                 no 
                 27 
                 57.4% 
                 6 
                 33.3% 
                 7 
                 53.8% 
                 0.006 
               
               
                 Spotting 
               
               
                 yes 
                 27 
                 57.4% 
                 6 
                 33.3% 
                 7 
                 53.8% 
               
               
                 no 
                 20 
                 42.5% 
                 12 
                 66.7% 
                 6 
                 46.1% 
                 0.006 
               
               
                   
               
             
          
           
               
                   
                 TOTAL 
                 GROUP A 
                 GROUP C 
                   
               
             
          
           
               
                   
                   
                 avg ± week 
                   
                 avg ± week 
                   
                 avg ± week 
                   
               
               
                   
                 N 
                 (min:max) 
                 N 
                 (min:max) 
                 N 
                 (min:max) 
                 P 
               
               
                   
               
               
                 Total duration of bleeding 
                 47 
                 13.9 ± 3.1  
                 18 
                 6.2 ± 3.3 
                 13 
                 18.5 ± 7.7  
                 0.013 
               
               
                 (days) 
                   
                  0:75 
                   
                  0:42 
                   
                  0:75 
               
               
                 Average intensity 
                 47 
                 0.9 ± 0.1 
                 18 
                 0.6 ± 0.2 
                 13 
                 1.0 ± 0.3 
                 0.055 
               
               
                   
                   
                 0:2 
                   
                   0:2.33 
                   
                 0:2 
               
               
                 Number of weeks of 
                 47 
                 2.9 ± 0.6 
                 18 
                 1.3 ± 0.6 
                 13 
                 3.3 ± 1.2 
                 0.007 
               
               
                 bleeding 
                   
                  0:12 
                   
                 0:9 
                   
                  0:11 
               
               
                 Total number of episodes 
                 47 
                 1.3 ± 0.3 
                 18 
                 0.6 ± 0.3 
                 13 
                 1.1 ± 0.5 
                 0.002 
               
               
                   
                   
                 0:7 
                   
                 0:6 
                   
                 0:7 
               
               
                   
               
               
                 None of the patients suffered from metrorrhagias during phase II 
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE V 
               
             
             
               
                   
               
               
                 Δ % 
                 TOTAL 
                 GROUP A 
                 GROUP C 
                   
               
             
          
           
               
                 Between C1 
                   
                 avg ± week 
                   
                 avg ± week 
                   
                 avg ± week 
                   
               
               
                 And C3 
                 N 
                 (min:max) 
                 N 
                 (min:max) 
                 N 
                 (min:max) 
                 P 
               
               
                   
               
               
                 A.L.A.T. 
                 43 
                 −23.1% ± 5.2% 
                 17 
                 −19.0% ± 3.8% 
                 11 
                  −31.2% ± 13.2% 
                 0.936 
               
               
                   
                   
                 −88.2%:85.7% 
                   
                 −50%:7.1%  
                   
                 −88.2%:29.4% 
               
               
                 F.S.H. 
                 45 
                 −74.1% ± 4.9% 
                 18 
                 −72.2% ± 5.5% 
                 12 
                 −78.2% ± 9.6%  
                 0.405 
               
               
                   
                   
                 −98.4%:69.2% 
                   
                 −98%:24.8% 
                   
                 −98.4%:22.8% 
               
               
                 Estradiol (pg/ml) 
                 40 
                   432% ± 68.5% 
                 15 
                     567% ± 118.7% 
                 10 
                   609% ± 163.6% 
                 0.036 
               
               
                   
                   
                  −54%:1640% 
                   
                  −16%:1320% 
                   
                  −54.3%:1640% 
               
               
                   
               
               
                 A.L.A.T. = Alanine Aminotransferase Transaminase 
               
               
                 F.S.H.—Follide Stimulating Hormone 
               
             
          
         
       
     
     The relative variation in estradiol level is quite important in the two groups (Δ%=567% in group A and 609% in group C), p=0.04 
     Table VI illustrates another study which was carried out. In this other study, it is interesting to note that with nomegestrol acetate, the percentage of patients with absolute amenorrhea (including all forms of estrogenotherapy) is greater from the 3rd month of treatment: 42.5% against 33.3%. In the treatment mentioned above, one must wait until the 12th month of treatment to obtain this percentage of 42% of patients with amenorrhea which was obtained here from 3 months, whilst the populations are comparable in terms of age, weight and length of time since the menopause. In addition, there exists in the previous study, an estrogen effect which is not found in this other study. On the other hand, this study reveals a dosage effect of progestative during the last 9 months of treatment (the lower the dose of progestative the better the cycle is controlled). 
     Finally, it is interesting to note that no correlation exists between the existence of an amenorrhea at 6 months and the endometrial thickness measured by endovaginal echography; this thickness varying by +1.6 mm on average over 6 months in the 2 treatment groups. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE VI 
               
               
                   
               
               
                 Characteristics of the patients 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 TOTAL 
                 GROUP A 
                 GROUP C 
                   
               
             
          
           
               
                   
                   
                 avg ± week 
                   
                 avg ± week 
                   
                 avg ± week 
                   
               
               
                   
                 N 
                 (min:max) 
                 N 
                 (min:max) 
                 N 
                 (min:max) 
                 P 
               
               
                   
               
               
                 Age 
                 54 
                 54.9 ± 0.6 
                 19 
                 53.9 ± 0.8 
                 17 
                 54.9 ± 1.1 
                 0.321 
               
               
                   
                   
                 45:64 
                   
                 48:60 
                   
                 45:63 
               
               
                 Age of 
                 54 
                 56.1 ± 5.0 
                 19 
                 48.5 ± 7.7 
                 17 
                 50.7 ± 7.7 
                 0.309 
               
               
                 amenorrhea (months) 
                   
                  7:134 
                   
                  12:108 
                   
                  11:121 
               
               
                 Weight (kg) 
                 54 
                     60 ± 1.1 
                 19 
                 61.6 ± 1.2 
                 17 
                 60.8 ± 2.2 
                 0.149 
               
               
                   
                   
                 42:85 
                   
                 51:70 
                   
                 12:76 
               
               
                 Height 
                 54 
                  1.61 ± 0.01 
                 19 
                  1.62 ± 0.01 
                 17 
                  1.61 ± 0.02 
                 0.449 
               
               
                   
                   
                 1.47:1.75 
                   
                 1.57:1.75 
                   
                 1.47:1.75 
               
               
                 Quetelet&#39;s index 
                 54 
                 23.1 ± 0.4 
                 19 
                 23.3 ± 0.4 
                 17 
                 23.5 ± 0.7 
                 0.3182 
               
               
                 (kg/m 2 ) 
                   
                 17.1:31.2 
                   
                 19.7:25.6 
                   
                 17.5:28.7 
               
               
                 SBP (mmHg) 
                 54 
                 123.9 ± 1.5  
                 19 
                 127.9 ± 2.5  
                 17 
                 121.2 ± 2.5  
                 0.136 
               
               
                   
                   
                 100:140 
                   
                 110:140 
                   
                 110:140 
               
               
                 DBP (mmHg) 
                 54 
                 74.6 ± 1.2 
                 19 
                 76.8 ± 2     
                 17 
                 73.5 ± 2.3 
                 0.386 
               
               
                   
                   
                 60:90 
                   
                 60:90 
                   
                 60:90 
               
               
                   
               
             
          
           
               
                 H.R.T. 
                   
                 TOTAL 
                   
                 GROUP A 
                   
                 GROUP C 
                   
               
             
          
           
               
                 Previous HRT&#39;s 
                 N 
                 % 
                 N 
                 % 
                 N 
                 % 
                 P 
               
               
                   
               
               
                 yes 
                 17 
                 31.5% 
                 9 
                 47.4% 
                 14 
                 82.3% 
               
               
                 no 
                 37 
                 68.5% 
                 10 
                 52.6% 
                 8 
                 17.7% 
                 0.046 
               
               
                   
               
               
                 HRT = Hormone Replacement Therapy 
               
               
                 SBP = Systolic Blood Pressure 
               
               
                 DBP = Diasystolic Blood Pressure

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