PL203438B1 - Pharmaceutical composition containing dehydroepiandrosterone, a derivative of triphenylethylene and a pharmaceutically acceptable excipient, kit and use of dehydroepiandrosterone - Google Patents

Description

DESCRIPTION OF THE INVENTION The invention relates to a pharmaceutical composition comprising a triphenylethylene derivative and a pharmaceutically acceptable excipient, a kit and the use of dehydroepiandrosterone. Human beings have the unique trait, along with some other primates, of having adrenal glands that secrete large amounts of the precursor steroids, dehydroepiandrosterone sulfate (DHEA-S) and dehydroepiandrosterone (DHEA), which transform into androstenedione (4). -dion), and then into active androgens and / or estrogens in peripheral tissues (Labrie et al., in Important Advances In Oncology. Ed. VT de Vita, S. Hellman, SA Rosenberg. JB Uppincott, Philadelphia, 193- 217, 1985; Labrie, Mol. Cell. Endocrinol. 78: C113-C118, 1991; Labrie, et al. In Signal Transduction in Testicular Cells. Ernst Schering Research Foundation Workshbp Ed. V. Hansson, FO Levy, K. Tasken. Springer-Verlag, Berlin-New York (Supl. 2), pp. 185-218,1996; Labrie et al., Steroids, 62: 148-158,1997). In a recent study (Labrie, et al., J. Clin. Endocrinol. Metab., 82: 2403-2409, 1997), we reported a sharp decrease in the amount of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), androstenedione-5-ene-3β, 17β-diol (5-diol), 5-diol-S, fatty acid esters of 5-diol and androstenedione in men and women aged 20 and 80 years. Despite the significant decline in endogenous androgens in women during aging, the use of androgens in postmenopausal women has been limited mainly because of concerns about an increased risk of cardiovascular disease, based on previous studies showing an unfavorable lipid profile with androgens. Recent studies, however, have not shown a significant effect of combined estrogen and androgen therapy on plasma levels of cholesterol, triglycerides, HDL, LDL, and HDL / LDL ratio compared to estrogen alone (Sherwin et al., Am. J. Obstet. Gynecol., 156: 414-419, 1987). In line with these observations, we have shown that DHEA, a compound with a predominantly anenic effect, does not show a markedly deleterious effect on the plasma lipid profile (Diamond et al., J. Endocrinol., 150: S43-S50. , 1996). Similarly, no changes in cholesterol, its subfraction or triglyceride concentrations were found during therapy with estradiol alone after 6 months of therapy with estradiol + testosterone implants (Burger et al., Br. Med. J. Clin. Res. Ed., 294: 936) -937, 1987). It should be noted that a male study found an inverse correlation between plasma DHEA-5 and low-g ester lipoproteins (Parker et al., Science, 208: 512-514, 1980). Recently, a correlation has been found between low plasma testosterone and DHEA levels and increased visceral adiposis as a parameter of higher cardiovascular risk (Tchernof et al., Metabolism, 44: 513-519, 1995). 5-diol is a compound biosynthesized from DHEA by the action of reductive 17 ß-hydroxysteride dehydrogenase (17 ß-HSD) and is a poor estrogen. It shows 85 times lower affinity than that of 17 ß-estradiol (E2) for the estrogen receptor in the anterior cytosol of the rat pituitary gland (Simard and Labrie, J. Steroid Biochem., 26: 539-546, 1987), confirming in addition, data obtained for the same parameter in human uterine and breast cancer tissue (Kreitmann and Bayard, J. Steroid Biochem., 11: 1589-1595, 1979; Adams et al., Cancer Res., 41: 4720-4926, 1981; Poulin and Labrie, Cancer Res. 46: 4933-4937, 1986). However, at concentrations ranging from plasma levels in adult women, 5-diol promotes cell proliferation and increases progesterone receptor levels in ZR-75-1 human breast cancer cells (Poulin and Labrie, Cancer Res., 46 : 4933-4937, 1986) and enhances estrogen-dependent 52 kDa glycoprotein synthesis in MCF-7 cells (Adams et al., Cancer Res., 41: 4720-4926, 1981). As mentioned above, it is known that plasma levels of DHEA, DHEA-S and 5-diol decline with age, and accordingly, there is a strong age-dependent reduction in androgen and estrogen production in peripheral target tissues. Such changes in the secretion of DHEA-S and DHEA cause a significant decrease in the biochemical and cellular functions stimulated by sex steroids. As a result, DHEA and DHEA-S have recently been used to treat a number of conditions that are associated with a decline and / or imbalance in sex steroid levels. Osteoporosis, a condition that occurs in both men and women, is associated with a decline in androgel and estrogen levels. Estrogens have been shown to reduce bone degradation quickly, while androgens have been shown to build bone mass. However, the estrogen therapy commonly used for osteoporosis requires the addition of progestins to counteract uterine hyperplasia and the risk of estrogen-induced uterine cancer. Moreover, because estrogens and progestins are likely to increase the risk of breast cancer (Bardon et al., J. Clin. Endocrinol. Metab., 60: 692-697, 1985; Colditz et al., N. Engl. J. Med., 332: 1589-1593, 1995), the use of estrogen-progestin substitution therapy is accepted by few women and usually for too short periods. PL 203 438 B1 3 Some studies suggest that osteoporosis is a clinical manifestation of androgen deficiency in men (Baran et al., Calcif. Tissue Res. 26: 103-106, 1978; Odell and Swerdloff, West J. Med. 124: 446-475, 1976; Smith and Walker, Calif. Tissue Res. 22 (Suppl. ): 225-228,1976). Androgen therapy, as noted with nandrolone decanoate, has been shown to increase the bone mineral density of postmenopausal women (Need et al., Arch. Intern. Med., 149: 57-60, 1989). Treatment of postmenopausal women with nandrolone increases the content of sc minerals in the cortex (Need et al., Clin. Orthop. 225: 273-278, 1987). Androgenic side effects were recorded in 50% of patients, however. Such data are interesting because, although almost all current treatments are limited to reducing bone loss, an increase in bone mass has been found with the use of the anabolic steroid nandrolone. A similar androgen stimulation of bone formation has been proposed in a hypogonadic male (Baran et al., Calcif. Tissue Res. 26: 103, 1978). The stimulation of bone formation in postmenopausal women treated with DHEA for 12 months is described by Labrie et al. (J. Clin. Endocrinol. 82: 3498-3505,1997). DHEA (450 mg / kg, bw, 3 times weekly) significantly delayed the appearance of breast tumors in C3H mice genetically bred to develop breast cancer (Schwartz, Cancer Res. 39: 1129-1132, 1979). In addition, the risk of bladder cancer increases in men who have lower plasma levels of DHEA (Gordon et al., Cancer Res. 51: 1366-1369, 1991). United States Patent Application No. 5,550,107 relates to a method of treating breast and uterine cancer in heat-susceptible blood-bearing animals, which method may include inhibition of hormonal ovarian secretion by surgery (ovariectomy) or chemistry (use of an LHRH agonist, eg [D-Trp 6, des-Gly-NH 2 10] LHRH-ethylamide or an antagonist) as part of a combination therapy. Antiestrogens, androgens, progestins, inhibitors of sex steroid formation (especially 17 ß-hydroxysteride catalyzed dehydrogenases or aromatases in the production of sex steroids), inhibitors of prolactin secretion, growth hormone secretion and ACTH secretion are discussed. The equivalent has been published under International Publication Number WO 90/10462. Moreover, cardiovascular disease is associated with a decrease in plasma levels of DHEA and DHEA-5, and it has been proposed that DHEA and DHEA-5 prevent or treat these conditions (Barrett-Connor et al., N. Engl. J. Med. 315: 1519-1524, 1986). In adult Sprague-Pawley rats, Schwartz (in Kent, Geriatrics 37: 157-160, 1982) found that Ia weight decreased from 600 to 550 g with DHEA without compromising food intake. Schwartz (Cancer 39: 1129-1132, 1979) noted that C3H mice receiving DHEA (450 mg / kg, 3 times a week) gained significantly less weight and were older than the control animals. less fat in the body and they were more active. Weight reductions were achieved without loss of appetite or food restriction. In addition, DHEA can prevent weight gain in animals raised to adulthood (Kent, Geriatrics 37: 157-160, 1982). Administration of DHEA to lean Zucher rats decreased weight gain la despite higher food intake. The treated animals had smaller pillows of fat, which generally suggests that DHEA increases food metabolism, reducing weight gain and fat accumulation (Svec et al., Proc. 2 nd int Conf. Cortisol and Anti-Cortisols, Las Vegas, Nevada, USA, p. 56 abst., 1997). Obesity is increased in mutant AVY mice (Yen et al., Lipids 12: 409-413, 1977) and in Zucker rats (Cleary and Zisk, Fed. Proc. 42: 536, 1983). The DHEA-treated C3H mice had a lower appearance than the controls (Schwartz, Cancer Res, 39: 1129-1132, 1979). DHEA reduces the onset of disease in cholesterol-fed rabbits (Gordon et al., J. Clin. Invest 82: 712-720, 1988; Arad et al., Arteriosclerosis 9: 159-166, 1989). In addition, high plasma concentrations of DHEA-S have been reported to protect against death from cardiovascular disease in men (Barrett-Connor et al., N. Engl. J. Med. 315: 1519-1524, 1986). The circulating levels of DHEA and DHEA-S have therefore been found to be inversely correlated with cardiovascular mortality (Barrelpt-Connor et al., N. Engl. J. Med. 315: 1519-1524). , 1986) and decreases in parallel with a decrease in immunocompetence (Thoman and Weigle, Adv. Immunol. 46: 221-222, 1989). A human study found an inverse correlation between serum DHEA-S and low lipoprotein (LDL) g esters (Parker et al., Science 208: 512, 1980). DHEA uses as well as the benefits of androgen and estrogen therapy are discussed in WO 94/16709. It is not believed that the correlations found in the art suggest effective treatments or prophylaxis, or are free from undesirable side effects, such as combination therapies. The present invention relates to a pharmaceutical composition containing a dehydroepiandrosterone, a selective estrogen receptor modulator and a pharmaceutically acceptable excipient which comprises: a) a pharmaceutically acceptable excipient, diluent or carrier; b) a therapeutically effective amount of dehydroepiandrosterone, c) a therapeutically effective amount of a triphenylethylene derivative of the general formula wherein D is -OCH 2 CH 2 N (R 3) R 4 or -CH = CH-COOH, R 3 and R 4 independently selected from the group consisting of C 1 -C 4 alkyl or R 3, R 4 and the nitrogen atom to which they are bound together form a ring structure selected from the group consisting of pyrrolidine, dimethyl-1-pyrrolidine , methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino and morpholino; wherein E and K are independently hydrogen or hydroxy; where J is hydrogen or halogen. Preferably, the pharmaceutical composition according to the invention comprises a compound GW-5638 of the following formula as a triphenylethylene derivative: The invention relates to a kit wherein a first container contains a therapeutically effective amount of dehydroepiandrosterone and comprises a second container containing a therapeutically effective amount a derivative of triphenylethylene. Preferably, the kit as a triphenylethylene derivative comprises the compound GW-5638 of the following formula: The present invention relates to the use of dehydroepiandrosterone in the manufacture of a medicament for the treatment or reduction of the risk of acquiring osteoporosis in combination with a therapeutically effective amount of the triphenylethylene derivative. Preferably the compound GW-5638 of the following formula is used as the triphenylethylene derivative. Figures 1 and 2 show the administration of SERM alone to produce a significant prophylactic effect, even in the absence of the administered precursors. As used herein, a selective estrogen receptor modulator (SERM) is a compound that, directly or through an active metabolite, acts as an estrogen receptor antagonist ("antiestrogen") in the breast tissue, producing estrogenic or estrogen-like effects on bone tissue. and blood cholesterol levels (ie, by lowering plasma cholesterol). Non-steroidal compounds that act as estrogen receptor antagonists in vitro or in human or rat breast tissue (especially if the compound acts as an anti-estrogen on human breast cancer cells) may act as SERMs. Conversely, steroidal antiestrogens can act as SERMs because they have no beneficial effect on plasma cholesterol. Non-steroidal antiestrogens that have been tested and found to act as SERMs include EM-800, EM-01538, Raloxifene, Tamoxifene, and Droloxifene. They tested the seventh antiestrogen ICI 182780 and found that it did not act as a SERM. SERMs may be administered at the same dosages as known in the art when these compounds are used as antiestrogens. We also noted a correlation between a favorable effect of SERMs on plasma cholesterol and a favorable estrogenic or estrogen-like effect on bone and plasma lipids. SERMs that have benefited all of these parameters in our studies included bone mass, cholesterol and triglyceride levels. Without being bound by theory, it can be seen that SERMs, many of which preferably have two aromatic rings bound by one to two carbon atoms, can interact with the estrogen receptor by virtue of the above part of the molecule that is best recognized by the receptor. Preferred SERMs have side chains that can selectively display antagonistic tendency in breast tissue without displaying significant antagonistic tendency in other tissues. Thus, SERMs can act as desired antiestrogens in the breast, while unexpectedly and as desired act as estrogens (or exhibit eptrogen-like activity) in bones and blood (where they favorably influence a on lipid and cholesterol concentrations). The beneficial effect on cholesterol and lipid translates into a beneficial effect on the life of the etery, which is adversely affected by improper cholesterol and lipid levels. All these diseases treated as discussed herein respond, preferably to androgens. Rather than using androgens as such, applicants use sex steroid precursors such as DHEA, DHEA-S, 5-diol, or prodrugs converted to any such sex steroid precursor. In vivo, DHEA-S converts to DHEA, which in turn converts to 5-diol. It can be understood that any tissue that responds favorably to one of them may respond favorably to the other. The active metabolite prodrug forms are well known in the art. See, e.g., H. Bundgaard "Design and Application of Prodrugs" (in: A Textbook of Drug Design and Development. Ed. H. Bundgaard and P. Krogggaard-Larsen; Harwook Academic Publishers GmfH, Chur: Switzerland, 1991), to be incorporated herein by reference. In particular, see pp. 154-155 describing the different functional groups of active metabolites and the corresponding groups of prodrugs that convert in vivo to each of the three functional groups. When the levels of the sex steroid precursor in patients are elevated, this can usually be done by administering such a precursor or by administering a precursor to such a precursor. Using precursors instead of androgens reduces undesirable androgenic activity in non-target tissues. Tissues convert precursors such as DHEA into androgens only through a natural and more regulated process. A significant percentage of androgens are formed locally in the peripheral tissues and to a varying extent in different tissues. Crayfish react unfavorably to the estrogenic activity of SC. On the other hand, osteoporosis, hyperciolesterolemia, hyperlipidemia, and have ever had a history of reacting to, preferably, estrogenic or estrogen-like activity. By using SERMs, desired effects are achieved in target tissues without undue influence in certain other tissues. For example, SERMs may have beneficial estrogenic effects on bone (or on lipid or cholesterol) avoiding adverse estrogenic effects on the breast. Thus, the precursor and the SERM have a favorable effect on the target tissues while minimizing the adverse effects on certain other tissues. Moreover, there are significant synergies when using both together. For example, estrogens and androgens exert a beneficial effect on osteoporosis by various mechanisms (estrogen reduces bone resorption, androgen helps in bone formation). The combination of the invention provides the bone with the beneficial effects of estrogen or estrogen-like effects through the SC SERM activity, and also provides the beneficial androgen through the local conversion of the precursor to androgen in bone. The precursor is also believed to provide estrogen. The same is true of lipid or cholesterol control (useful for treating or preventing disease). Similar synergy occurs in breast, endometrial, ovarian or uterine cancers, where the SERM provides the desired anti-estrogenic activity and the precursor provides the desired androgenic activity (with any random conversion of the precursor to estrogen moderated by the anti-estrogen). Undesirable effects are also mitigated in a synergistic manner by the combination. For other diseases, any other effects on the breast tissue that could result from the estrogen produced by the precursor (when the precursor is used to promote androgenic effects) are also mitigated by anti-estrogenic action of SERMs in breast tissue. In some cases, progestins are added to achieve a further androgenic effect. Progestins may be used at the low doses known in the art without adversely affecting receptors other than androgen receptors (eg, glucocorticoid receptors). They are so relatively free of unwanted androgenic side effects (such as the faces of new patients). The preferred SERMs apply to: (1) all disease states; (2) for curative and prophylactic uses; and (3) to preferred pharmaceutical compositions and kits. A preferred precursor is DHEA. A patient in need of treatment or reduction of the risk of an attack for a given disease is one who has also been diagnosed with or is susceptible to attack by such disease. Unless stated otherwise, the preferred dosage of the active compounds (concentrations and modes of administration) is identical for therapeutic and prophylactic purposes. The dosage for each active ingredient discussed herein is the same regardless of the disease being treated (or the disease whose severity of attack has been reduced). Unless otherwise stated or where the context so requires, doses refer to the weight of the active compounds without pharmaceutical excipients, dilutions of excipients, carriers or other ingredients, although such additional ingredients are usefully combined with as shown in the examples. Any dosage form (capsule, tablet, injection, or the like) commonly used in the pharmaceutical industry is suitable for use herein and the terms "excipient," "diluent" or "carrier" include such inactive ingredients as It is combined typically with the active ingredients in such dosage forms in industry. For example, conventional capsules, pills, intestinal coatings, solid or liquid diluents or excipients, flavors, preservatives or the like can be used. All of the active ingredients used in any of the therapies discussed herein can be formulated into pharmaceutical compositions that include one or more other active ingredients. Alternatively, each can be administered separately, but at the same time over time that the patient eventually exhibits elevated blood levels or otherwise benefits from each of the active ingredients (or strategy) at the same time. Preferably, one or more active ingredients are formulated in a single pharmaceutical composition. Preferably, a kit is provided comprising at least two separate containers, the contents of the at least one container differing, in whole or in part, from the contents of the at least one other container with respect to the active ingredients. contained therein. The combination therapies discussed herein include the use of an active ingredient (combination) in the manufacture of a medicament for the treatment (or risk reduction) of a given disease, where treatment or prevention further comprises another active ingredient of the combination. Effect of treatment with DHEA (10 mg, transdermal, once daily) or EM-800 (75 µg, po, once daily) alone or in combination for 9 months after onset of DM-BA-induced rat breast cancer over a follow-up period of 279 days. Data are expressed as a percentage of the total number of animals in each group. Figure 2 shows the effect of treatment with DHEA (10 mg, transdermal, once daily) or EM-800 (75 µg, po, once daily) alone or in combination for 9 months with an average number of tumors on tumors in animals (A) and with average tumor size per tumor bearing rat (B) for the observation period 279 days. Data expressed as mean ± SEM. Figure 3 shows the effect of treatment with DHEA (10 mg, transdermal, once daily) or EM-800 (75 µg, po, once daily) alone or in combination for 9 months on plasma levels of triglyceride (A) and cholesterol (B). in a rat. Data expressed as mean ± SEM. **: P <0.01 to be experimental versus appropriate controls. Figure 4 shows: A) Effect of escalating doses of DHEA (0.3 mg, 1.0 mg or 3.0 mg) administered percutaneously twice daily on average ZR-75-1 tumor sizes in excised nude mice. etymi ovaries (OVX) supplemented with flaxseed estrone. Control OVX mice receiving the carrier alone are used as additional controls. The initial tumor size was taken as 100%. DHEA was administered transdermally (p. C.) In 0.02 ml of 50% ethanol - 50% propylene glycol solution on the dorsal skin. B) Effect of treatment with increasing doses of DHEA or EM-800 alone or in combination for 9.5 months on ZR-75-1 tumors in 0VX nude mice supplemented with estrone. **, p <and 0.01, treated versus control OVX mice supplemented with estrone. Figure 5 shows the effect of increasing oral doses of the antiestrogen EM-800 (15 µg, 50 µg or 100 µg) (A) or percutaneous administration of increasing doses of DHEA (0.3, 1.0 or 3.0 mg) of the combined with EM-800 (15 µg) or EM-800 (B) alone for 9.5 months at the average size of ZR-75-1 tumors in ovariectomized (OVX) nude mice supplemented with estrone. The initial tumor size was taken as 100%. Control OVX mice receiving the carrier alone were used as additional control animals. Estrone was administered subcutaneously at a dose of 0.5 µg once daily, while DHEA was dissolved in 50% ethanol - 50% propylene glycol and applied to the dorsal skin surface twice daily in a volume of 0.02 ml. It is also made from a comparison with OVX animals receiving the carrier itself. Figure 6 shows the effect of a 12-month treatment with dehydroepiandrosterone (DHEA) alone or in combination with Flutamide or EM-800 on trabecular bone coverage in ovariectomized rats. Untouched animals are added as additional control animals. Data are presented as mean ± SEM ** p <0.01 versus OVX control. Figure 7 shows the effect of 12 months treatment with dehydroepiandrosterone (DHEA) alone or in combination with Flutamide or EM-800 on trabecular number in ovariectomized rats. The intact eta eta are added as additional control animals. Data are presented as mean ± SEM ** p <0.01 versus OVX control. Figure 8 shows the proximal tibial epiphyses of non-woven control (A), ovariectomized (B) and ovariectomized control rats treated with DHEA alone (C) or in combination with Flutamide (D) or EM-800 (E). Note the reduced number of trabecular bones (T) in control ovariectomized animals (B) and the significant increase in trabecular bone volume (T) induced after DHEA administration (C). The addition of Flutamide to DHEA partially blocked the effects of DHEA on the trabecular bone volume (D), while the combination of DHEA and EM-800 provided complete protection against ovariectomy related bone loss. Modified Tricolor Massson-Goldner, magnification x 80. T: Trabeculae, GP: Growth Plate. Figure 9 shows the effect of increasing doses (0.01, 0.03, 0.1, 0.3 and 1 mg / kg) of EM-800, EM-1538 and Raloxifene (EM-1105) administered orally daily for 4 days on cholesterol levels in ovariectomized rats. Figure 10 shows the effect of 34 weeks of treatment with dehydroepiandrosterone (DHEA) alone or in combination with EM-1538 (EM-652 · HCl) on the minerals in the lymphocytes in ovariectomized rats. Untouched animals are added as additional control animals. Data are presented as mean ± SEM ** p <0.01 versus OVX control. Figure 11 shows the combined effects of SERM (EM-652) and DHEA on parameters of menopause. No negative impact was expected. Figure 12 shows the plasma concentrations of DHEA (ng / ml) (Y-axis) as a function of time (X-axis) after a single oral absorption of the preferred sex steroid precursors (150 µmol / rat) in male rats. In box the AUC 24 hours of DHEA induced by these compounds is given. EM-760 dehydroepiandrosteren EM-900 androst-5-ene-3 ß, 17 ß-diol EM-1304 3-androst-5-ene-3 ß, 17 ß-diol acetate EM-1305-CS androst-5-eno diacetate -3 ß, 17 ß-diol EM-1397 3-acetate, 17-androst-5-ene-3 ß, 17 ß-diol EM-1400 androst-5-ene-3 ß dibenzoate, 17 ß-diol EM- 1410 androst-5-ene-3β-dipropionate, 17β-diol EM-1474-D androst-5-ene-3β dihemisuccinate, 17β-diol Figure 13 shows the plasma concentration of androst-5-ene-3β, 17 ß-diol (ng / ml) (Y-axis) as a function of time (X-axis) after oral absorption of a sex steroid precursor (150 µmol / rat) in male rats. The AUC 24 hours of androst-5-ene-3β, 17β-diol induced by these compounds is given in the box. EM-760 dehydroepiandrosterone EM-900 androst-5-ene-3 ß, 17 ß-diol EM-1304 3-androst-5-ene-3 ß, 17 ß-diol acetate EM-1305-CS androst-5-eno diacetate -3 ß, 17 ß-diol EM-1397 3-acetate, 17-androst-5-ene-3 ß, 17 ß-diol EM-1400 androst-5-ene-3 ß dibenzoate, 17 ß-diol EM- 1410 androst dipropionate: -5-ene-3β, 17β-diol EM-1474-D androst-5-ene-3β dihemisuccinate, 17β-diol Estrogens are well known to stimulate the proliferation of breast epithelial cells, and the same cell proliferation is believed to increase the risk of cancer by the accumulation of random genetic errors that may cause cancer (Preston Martin et al., Cancer. Res. 50: 7415-21, 1990). Based on this concept, anti-estrogens have been introduced to prevent breast cancer in order to reduce the rate of cell division stimulated by estrogens. The loss of ovulation cyclicality found in female Sprague-Dawley rats after 10 months of life is accompanied by increased levels of estrogen and prolactin in the plasma and a decrease in plasma levels of androgen and progesterone (Lu et al., 61st Annual Meeting of the Endocrine Society) 106 (abst. # 134), 1979; Tang et al., Biol. Reprod. 31: 399-413, 1984; Russo et al., Monographs on Pathology of Laboratory Animals: Integument and Mammary Glands 252-266, 1989; Sortino and Wise, Endocrinology 124: 90-96, 1989; Cardy, Vet. Pathol. 28: 139-145, 1991). These hormonal changes, which occur spontaneously in aging female rats, are associated with multifocal hyperplasia and increased activity in the secretory activity of the acinar / follicular tissue, as well as with dilatation of the mammary gland canal and formation of cysts ( Boorman et al., 433,1990; Cardy, Vet. Pathol. 28: 139-145,1991). It should be mentioned that proliferative and neoplastic changes in the rat mammary gland are often accompanied by increased levels of estrogens and prolactin (Meites, J. Neural. Transm. 48: 25-42, 1980). Treatment with EM-800, SERM induces mammary gland atrophy, which is characterized by a decrease in the size and number of lobular structures and no evidence of secretory activity, which indicates a strong anti-estrogenic activity of sc EM-800 in the mammary gland (Luo et al. ., Endocrinology 138: 4,435 1144,1997). Treatment with DHEA, a sex steroid precursor, leads to an increase in plasma DHEA and 5-diol, while plasma levels of 4-dione, testosterone, dihydrotestosterone and estradiol increase and only moderately or more often remain unchanged, limiting intracellular biotransformation. e of this steroid precursor for peripheral tissues (Labrie et al., Mol. Cell. Endocrinol. 78: C113-C118, 1991). However, the stimulating effect of orally administered DHEA on the plasma levels of androgens such as testosterone and dihydrotestosterone has a greater amplitude than the effect on plasma estrogen levels, suggesting that DHEA is mainly transformed into androgens in these animals. This observation is in agreement with data obtained in women where the formation of androgens from DHEA was a more important pathway than the conversion of DHEA to estrogens (Morales et al., J. Clin. Endocrinol. Metab. 78: 1360-1367, 1994; Labrie et al., Ann. NY Acad. Sci. 774: 16-28,1995; Labrie et al., Stroids 62: 148-158,1997). Knowing about the above-described strong anti-estrogenic activity arising from the atrophy of the mammary gland, and the dominant androgenic effect of DHEA on the mammary gland, the histomorphological changes seen in animals treated with the combination of SERM and the sex steroid precursor explained That the best androgenic androgenic effect of DHEA in the rat mammary gland is best unmatched. PL 203 438 B1 9 More importantly, it was noticed that androgens exerted direct anti-proliferative activity on the growth of human ZR-75-1 breast cancer cells in vitro and that this androgen inhibitory effect is added to that of antiestrogens (Poulin and Labrie, Cancer Res. 46: 4933-4937, 1986; Poulin et al., Breast Cancer Res. Treat. 12: 213-225, 1988) ). Similar inhibitory effects have been observed in vivo on ZR-75-1 xenografts in nude mice (Dauvois et al., Cancer Res. 51: 3131-3135, 1991). Androgens have also been shown to inhibit the growth of DMBA-induced rat breast cancer, and this inhibition was reversed by co-administration of the pure antiandrogen Flutamide (Dauvois et al., Breast Cancer Res. Treat. 14: 299-306, 1989). Collectively, the present data indicate the involvement of the androgen receptor in the inhibitory effect of DHEA on breast cancer. Since antiestrogens and sex steroid precursors exert an inhibitory effect on breast cancer by different mechanisms, the combination of SERM (EM-800) and a sex steroid precursor (DHEA) has a stronger inhibitory effect than any other compound. Alone to the development of DMBA-induced rat breast cancer as shown in Figures 1 and 2. In fact, no DMBA-induced tumor was found at the end of the experiment in animals receiving DHEA and EM-800. The combination of a sex steroid precursor (DHEA) and SERM (EM-800) preserves the stimulating effect of DHEA on bone formation and enhances the inhibitory effect of the SERM (EM-800) itself on metabolism and bone resorption, as shown by a further decrease in urinary excretion of hydroxyproline and calcium with the combination of both compounds. We have shown that DHEA has beneficial effects on bones in female rats (Luo et al., Endocrinology 138: 4435-4444, 1997) and postmenopausal women (Labrie et al., J. Clin. Endocrinol. Metab. 82: 3498-3505, 1997). Thus, in unsealed female rats, DHEA therapy with increased bone mineral density (BMD) of the entire bone, the lumbar vertebrae, and the femur (Luo et al., Endocrinology 138: 4435-4444,1997). On the other hand, treatment with EM-800 had no significant effect on BMD in non-woven animals, although strong stimulatory effects were observed in ovariectomized rats (Martel et al., Unpublished data). Since EM-800 exerts such a stimulatory effect on BMD of the whole femoral vertebrae, the lumbar spine and the femur in ovariectomized rats, there is no significant stimulatory effect of EM-800 in intact animals. this may be because the sex steroids present in intact non-infected female rats have a maximal effect on BMD (Luo et al., Endocrinology 138: 4435-4444,1997). Similarly, the lack of a significant effect of EM-800 in ovariectomized rats already consuming DHEA is probably due to the maximal stimulating effects exerted by androgens (and possibly estrogens) synthesized in bone cells from exogenous DHEA. Estrogens are known to lower plasma cholesterol levels but increase or not affect plasma triglyceride levels (Love et al., Ann. Intern. Med. 115: 860-864, 1991; Walsh et al. ., New Engl. J. Med. 325: 1196-1204, 1991; Barrett-Connor, Am. J. Med. 95 (Suppl. 5A): 40S-43S, 1993; Russell et al., Atherosclerosis 100: 113- 122, 1993; Black et al., J. Clin. Invest. 93: 63-69, 1994; Dipippo et al., Endocrinology 136: 1020-1033, 1995; Ke et al., Endocrinology 136: 2435-2441, 1995 ). Figure 3 shows that EM-800 has a hypocholesterolemic and hypotriglyceridemic activity in the rat, thus showing its unique effect on a plasma lipid profile which is very different from that of other SERMs such as tamoxifene ( Bruning et al., Br. J. Cancer 58: 497-499, 1988; Love et al., J. Natl. Cancer Inst. 82: 1327-1332,1990; Dipippo et al., Endocrinology 136: 1020-1033, 1995; Ke et al., Endocrinology 136: 2435-2441,1995), droloxifene (Ke et al., Endocrinology 136: 2435-2441, 1995) and raloxifene (Black et al., J. Clin. Invest. 93) : 63-69,1994). The combination of DHEA and EM-800 retained the hypocholesterolemic and hypotriglyceridemic effects of EM-800, suggesting that such a combination may have beneficial effects on plasma lipids. It should be noted that the plasma lipid profile is significantly different in rats and humans. However, since the estrogen receptor mediation mechanism is involved in the hypocholesterolemic effect of estrogens, such as those of antiestrogens (Lundeen et al., Endocrinology 138: 1552-1558, 1997), the rat remains a useful model for studying the effects of lowering estrogens. consuming cholesterol levels, estrogens and "anti-estrogens" in humans. Briefly, the above-described data clearly show the effects of the combination of SERM (EM-800) and a sex steroid precursor (DHEA) on the development of DMBA-induced breast cancer, as well as the protective effect of such a combination on bone mass. and plasma lipids. These data suggest an additional beneficial effect of such a combination in the treatment and prevention of osteoporosis while improving the lipid profile. We also investigated the potential interactions of the inhibitory effect of the new antiestrogen (EM-800) with the action of the steroid precursor (DHEA) on the growth of the human ZR-75-1 breast cancer in nude mice xenografts by the combined administration of two drugs. Figures 4 and 5 show that DHEA alone, at the doses used, caused 50 to 80% inhibition of tumor growth, while the almost complete inhibition of tumor growth achieved with a low dose of antiestrogen was not interfered with by DHEA. The limitations of bone mineral density (BMD) measurements are well known. For example, BMD measurements showed no changes in rats treated with the steroid antiestrogen ICI 182780 (Wakeling, Breast Cancer Res. Treat. 25: 1-9, 1993), while inhibitory changes were histomorphometric (Gallagher et al. ., Endocrinology 133: 2787-2791,1993). Similar differences have been reported for Tamoxifene (Jordan et al., Breast Cancer Res. Treat. 10: 31-35, 1987; Sibonga et al., Breast Cancer Res. Treatm. 41: 71-79, 1996). It should be pointed out that the reduced bone mineral density is not the only one, and the abnormality is related to the reduced bone strength. (Guidelines for preclinical and clinical evaluation of agents used in the prevention or treatment of postmenopausal osteoporosis. Division of Metabolism and Endocrine Drug Products, FDA, May 1994). It is therefore important to analyze the changes in the biochemical parameters of bone metabolism induced by various compounds and therapies in order to gain a better understanding of their effects. It is especially important to point out that the combinations of DHEA and EM-800 exerted unexpected beneficial effects on important biochemical parameters of bone metabolism. In fact, DHEA alone did not influence the urinary hydroxyproline / creatinine ratio, a marker of bone resorption. Furthermore, the lack of effect of DHEA can be detected in daily urinary excretion, et al., Endocrinology 138: 4435-4444, 1997). EM-800, on the other hand, lowered the urinary hydroxyproline / creatinine ratio by 48%, while, like DHEA, the effect of EM-800 on urinary calcium or phosphorus excretion was not seen. Moreover, EM-800 had no effect on the plasma levels of alkaline phosphatase activity, a marker of bone formation, while DHEA increased the parameter value by about 75% (Luo et al., Endocrinology 138: 4435-4444, 1997). One of the unexpected effects of the combination of DHEA and EM-800 relates to the urinary hydroxyproline / creatinine ratio, a marker of bone resorption, which decreased by 69% when DHEA and EM-800 were combined, and this was statistically different (p <0.01) from 48% inhibition obtained by EM-800 alone, while DHEA alone showed no effect. Thus, the addition of DHEA to EM-800 increases by 50% the inhibitory effect of EM-800 on bone reabsorption. Importantly, another unexpected effect of adding DHEA to EM-800 was an approximately 84% decrease in the amount of calcium in the urine (from 23.17 ± 1.55 to 3.71 ± 0.75 µmol / 24 hours / 100 g (p <0.01) and a 55% decrease in the amount of phosphorus in urine (from 132.72 ± 6.08 to 59.06 ± 4.76 μmol / 24 hours / 100 g (p <0.01), respectively (Luo et al., Endocrinology 138: 4435-4444,1997). Table 1 Urine Plasma Wap group n (µmol / 24 h / 100 g) Phosphorus (µmol / 24 h / 100 g) HP / Cr (µmol / mmol) tALP (IU / l) Control 23.17 ± 1, 55 132.72 ± 6.08 13.04 ± 2.19 114.25 ± 14.04 DHEA (10 mg) 25.87 ± 3.54 151.41 ± 14.57 14.02 ± 1.59 198, 38 ± 30.76 * EM-800 (75 μg) 17.44 ± 4.5 102.03 ± 25.13 6.81 ± 0.84 ** 114.11 ± 11.26 HEA + EM-800 3, 71 ± 0.75 ** 59.06 ± 4.76 ** 4.06 ± 0.28 ** 204.38 ± 14.20 ** It is interesting that it is also noticed that the strong inhibitory effect of EM- 800 for plasma cholesterol is not prevented by concurrent treatment with DHEA (Luo et al., Endocrinology 138: 4435-4444, 1997). While Raloxifene and similar compounds prevent bone loss and a decrease in plasma cholesterol (like estrogens), it should be noted that, when Raloxifene was compared with Premarin for BMD, the effect of Raloxifene on BMD was ls labszy than z wp lyw Premarinu (Minutes of the Endocrinology and Metabolism Drugs Advisory Committee, PDA Thursday, Meeting # 68, November 20 th 1997). Due to its well-known adverse effects on breast and uterine cancer, the addition of estrogen to Raloxifene, EM-800 or other similar compounds is not an acceptable solution. PL 203 438 B1 11 These results obtained for the rat clearly show and that DHEA can give beneficial results that cannot be achieved with Selective Estrogen Receptor Modulator (SERM) alone, such as EM-800, Raloxifene, etc. While SERM limits its effects to inhibition of resorption. The addition of DHEA, 5-diol, DHEA-S is likely to stimulate bone formation (effect not found for SERM or estrogen) and a further reduction in bone resorption over, the effect obtained by EM-800. Importantly, the combination of EM-800 and DHEA in ovariectomized rats treated for 12 months has a beneficial effect on bone morphometry. The volume of the trabecular bone is particularly important for the strength of the bone and for the prevention of bone fractures. Thus, in the above-mentioned study, tibial trabecular bone volume increased from 4.1 ± 0.7% in ovariectomized rats to 11.9 ± 0.6% (p <0.01) for DHEA alone, while the addition of EM-800 to DHEA further increased the trabecular bone volume by 14.7 ± 1.4%, a value similar to that found in intact controls (Fig. 6). From a value of 0.57 ± 0.08 per mm in ovariectomized rats, DHEA treatment resulted in a 137% increase in the number of trabecular bones compared to ovariectomized control animals. The stimulating effect of DHEA achieved the result 1.27 ± 0.1 per mm, while the simultaneous treatment with EM-800 and DHEA resulted in an additional 28% increase in the number of trabecular bones (p <0.01) compared to that obtained with DHEA alone (Fig. 7). Likewise, adding EM-800 to DHEA therapy resulted in an additional 15% (p <0.05) decrease in trabecular bone separation, compared to that obtained with DHEA alone, leading to values not different from those observed in intact control animals. In addition to the numerical data shown in Figures 6 and 7, Figure 8 illustrates the increase in trabecular bone volume in the proximal epiphyseal tibia induced by DHEA in treated ovariectomized animals (C) compared to controls with ovariectomized animals (C). ovariectomized ovaries (B) as well as with partial inhibition of the stimulating effect of DHEA after adding Flutamide to DHEA therapy (D). On the other hand, administration of DHEA in combination with EM-800 resulted in the complete prevention of ovariectomy-induced osteopenia (E), with the trabecular bone volume being comparable to that observed in intact controls (A) . The bone loss seen in the menopause in women is likely related to an increase in bone resorption rate that is not fully compensated by a secondary increase in bone formation. Indeed, the parameters of bone formation and bone resorption increase in osteoporosis, and bone resorption and bone formation are inhibited by estrogen substitution therapy. The inhibitory effect of estrogen substitution on bone formation is probably due to the interconnected mechanism between bone resorption and bone formation. bone formation and formation such that the primary estrogen-induced reduction in bone resorption entails a reduction in bone formation (Parfitt, Calcined Tissue International 36 Suppl. 1: S37-S45, 1984). The strength of the spongy bone and the further resistance of the spongy bone depends not only on the total amount of the spongy bone, but also on the trabecular microstructure, the number of a, size and distribution of the trabeculae. The loss of ovulation function in postmenopausal women is accompanied by a significant decrease in the total volume of the trabecular bone (Melsen et al., Acta Pathologica & Microbiologica Scandinavia 86: 70-81, 1978; Vakamatsou et al., Calcified Tissue International 37: 594-597) , 1985), mainly associated with a decrease in the number and, to a lesser extent, the width of the trabeculae (Weinstein and Hutson, Bone 8: 137-142, 1987). In this study, the androgenic stimulating effect of DHEA was observed on almost all the examined bone histomorphometric parameters. DHEA thus caused a significant increase in the volume of the trabecular bone, as well as the number of trabeculae, while it decreased the trabecular surface area. The composition according to the invention may be suitable for administration in any conventional way, such as including but not limited to oral administration, subcutaneous injection, intramammary injection, or transdermal administration. The kit may contain suitable substances for oral administration, e.g. tablets, capsules, syrups and the like, and for transdermal administration, e.g. ointments, lotions, gels, creams, slow release patches and the like. . The applicant claims that administration of SERMs and sex steroid precursors may be used in the treatment and / or prevention of the development of osteoporosis, breast cancer, hypercholesterolemia, hyperlipidemia, or the disease. The active ingredient for transdermal or transmucosal administration is preferably present in an amount from 0.5% to 20% by weight of the total weight of the pharmaceutical composition, more preferably between 2 and 10%. DHEA or 5-diol should be present at a concentration of at least 7% for percutaneous administration. Alternatively, the active ingredient may be incorporated into a transdermal patch having structures known in the art, for example structures as set forth in EP 0 279 982. When formulated as a mask, lotion, gel or cream or similarly, the active compound is mixed with a suitable carrier which is compatible with the human skin or mucosa and which improves the percutaneous penetration of the compound through the skin or mucosa. Suitable carriers are known in the art. - days and include, among others, Klucel HP and Glaxal basics. Some are commercially available, eg, Glaxal base available from Glaxal Canada Limited Company. Other suitable media can be found in Koller and Buri, S.T.P. Pharma 3 (2), 115-124, 1987. The carrier is preferably one in which the active ingredient (s) is (s a) soluble at ambient temperature at the active ingredient concentration used. The carrier should be of sufficient viscosity to maintain the inhibitor on the localized surface of the skin or mucosa to which the composition has been applied, without dripping or evaporating for a period sufficient to ensure sufficient penetration of the precursor through the localized surface of the skin or mucosa and into the bloodstream where it will produce the desired clinical effect. The carrier is typically a mixture of several ingredients, e.g., pharmaceutically acceptable solvents and a thickening agent. A mixture of organic and inorganic solvents can improve the hydrophilic and lipophilic solubility of the sc, for example water and an alcohol such as ethanol. Preferred sex steroid precursors are dehydroepiandrosterone (DHEA) (available from Diosynth Inc., Chicago, Illinois, USA), its prodrugs (available from Steraloids, Wilton, New Hampshire, USA), 5-androstene-3 ß, 17 ß - diol and its prodrugs EM-1304 and EM-01474-D (available from Steraloids, Wilton, New Hampshire USA). Preferably the sex steroid precursor is formulated as an alcohol gel containing 2.0 to 10% caprylic-capric triglyceride (Neobee M-5); 10 to 20% hexylene glycol; 2.0 to 10% diethylene glycol monomethyl ether (Transutol); 2.0 to 10% Cyclomethicone (Dow Corning 345); 1.0 to 2% benzyl alcohol and 1.0 to 5.0% hydroxypropyl cellulose (Klucel HF). The carrier may also include various additives commonly used in creams and lotions and well known in the cosmetic and medical arts. For example, it can be used with perfumes, antioxidants, perfumes, gelling agents, thickening agents such as carboxymethyl cellulose, surfactants, stabilizers, extenders, colorants and other similar agents. When used for the treatment of systemic diseases, the site of application to the skin should be changed in order to avoid excessive local concentration of the active ingredient and possible overstimulation of the skin and lymph glands by androgenic metabolites of the sex steroid precursor . In the pharmaceutical composition for oral administration, DHEA or the other precursor is preferably present in a concentration between 5 and 98% by weight of the total weight of the composition, more preferably between 50 and 98%, especially between 80 and 98%. A single precursor such as DHEA may be the sole active ingredient, or alternatively, may be known by using multiple precursors and / or analogs thereof (e.g., combinations of DHEA, DHEA-S, 5-diol, or a combination of two or multiple compounds converted in vivo to DHEA, DHEA-S or 5-diol or a combination of DHEA or 5-diol and one or more analogues thereof that convert to DHEA or 5 - diol in vivo, etc. The level of DHEA in the blood is the final criterion for adequate dosing, which takes into account individual differences in absorption and metabolism. Preferably, the treating physician, especially at the beginning of the treatment, observes the complete reaction in - the individual patient and plasma DHEA levels (compared to the preferred plasma concentrations discussed above) and monitors the patient's overall response to treatment, adjusting doses as needed when metabolism or patient response to treatment is unusual. this one lends itself to an indefinite salty continuation expecting that DHEA and / or 5-diol therapy will simply maintain DHEA levels within a range similar to that naturally occurring in premenopausal women (plasma concentration between 4 and 10 µg per liter) or naturally young adult men (plasma concentrations between 4 and 10 µg per liter). The SERM compound or bisphosphonate and / or sex steroid precursor can also be known by the oral route and can be formulated with conventional pharmaceutical excipients, e.g. spray dried lactose, microcrystalline cellulose and magnesium stearate in tablets or capsules for use in oral administration. The active substance can be transformed into tablets or cores of yeast by mixing with a solid, powdery carrier such as sodium citrate, into calcium carbonate or dicalcium phosphate, and binding agents such as polyvinylpyrrolidone, gelatin or a cellulose derivative, possibly also adding lubricants such as magnesium stearate, sodium lauryl sulfate, "Carbowax" or polyethylene glycol. Of course, it is possible to add taste-improving substances in the case of oral administration forms. As further forms, closable capsules, e.g. made of hard gelatin, can be used, such as those with dosing soft gelatin capsules containing a softener or a plasticizer, e.g. glycerin. The closable capsules contain the active substance, preferably in the form of granules, for example in a mixture with fillers such as lactose, sucrose, mannitol, starches such as corn starch or amylopectin, cellulose derivatives or well-dispersed silicic acids In soft gelatin capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as vegetable oils or liquid polyethylene glycols. Milk, cream, gel or cream should be carefully rubbed into the skin so that no excess is visible, and the skin should not be washed in this region until most of the percutaneous penetration has taken place, preferably at least 4 hours, and more preferably at least 6 hours. The transdermal patch may be used to deliver a precursor by known techniques. It is typically applied for a much longer time, for example 1 to 4 days, but typically contacts the active ingredient over a smaller surface area, allowing slow and continuous delivery of the active ingredient. Several transdermal drug delivery systems have been developed and used to deliver the active ingredient. The rate of release is typically controlled by diffusion from a matrix or by the passage of the active ingredient through the controlling cell. The mechanical aspects of the transdermal devices are well known in rats and are explained, for example, in U.S. Patent Nos. 5,162. 037, 5 154 922, 5 135 480, 4 666 441, 4 624 665, 3 742 951, 3 797 444, 4 568 343, 5 064 654, 5 071 644, 5 071 657. For further explanation see the European description Patent Application No. 0 279 982 and United Kingdom Patent Application No. 2,185,187. The device may be of any general type known in the art including an adhesive matrix and reservoir transdermal delivery device. The device may include drug-containing matrices containing fibers that absorb the active ingredient and / or the carrier. In a reservoir device, the reservoir may be defined by a polymeric film impermeable to the carrier and the active ingredient. In the transdermal device, the device itself keeps the active ingredient in contact with the desired localized skin surface. In such a device, the viscosity of the carrier for the active ingredient is less important than that of a cream or gel. The solvent system for the transdermal device can include c, eg, oleic acid, linear alcohol lactate, and dipropylene glycol, or other solvent system known in the art. The active ingredient can be dissolved or suspended in a carrier. For adhesion to the skin, the transdermal patch can be placed on a surgical adhesive tape having a diaphragm hole in the center. The binder is preferably covered with a release liner and a cover to protect it from wear. Typical material suitable for release includes polyethylene and polyethylene coated paper, preferably silicone coated for easy removal. For the device to be used, the release liner is simply peeled off and the adhesive attached to the patient's skin. In U.S. Patent No. 5,135,480 to Bannon et al. describe an alternative device having non-adhesive means of fastening | device on the skin. Transdermal or mucosal delivery systems may also be used as new and improved delivery systems for the prevention and / or treatment of osteoporosis or other diseases which respond favorably to androgen and / or estrogen therapy. The selective estrogen receptor modulator has a molecular formula with the following features: a) two aromatic rings separated by 1 to 2 carbon atoms, both aromatic rings unsubstituted or substituted by a hydroxyl group or a group transformed in vivo in hydroxy; and b) a side chain containing an aromatic ring and a functional group of a tertiary amine or a salt thereof. One of the preferred SERMs is EM-800 discussed in PCT / CA96 / 00097 (WO 96/26201). The molecular structure of EM-800 is as follows: Another preferred SERM is EM-01538: EM-1538 (so called EM-652 HCl) is the hydrochloride of the powerful antiestrogen EM-652, compared to EM-800, EM -1538 is simpler and easier in the synthesis of salts. It is also easy to separate, purify, crystallize and show good durability in a solid state. When either EM-800 or EM-1538 are administered, they are considered to produce the same active compound in vivo. Other preferred SERMs include Tamoxifene ((Z) -2- [4- (1,2-diphenyl-1-butenyl)] -N, N-dimethylethanamine) (available from Zeneca, UK), Toremifene (available from from Orion-Farmos Pharmaceuticla, Finland, or Schering-Plow), Droloxifene and CP-336156 (cis-1R- [4'-pyrrolidine-ethoxyphenyl] -2S-phenyl-6- hydroxy-1,2,3, 4, -tetrahydronaphthalene, D - (-) - tartrate) (Pfizer Inc., USA), Raloxifene (Eli Lilly and CO., USA), LY 335563 and LY 353381 (Eli Lilly and Co., USA), Iodoxifene (SmithKline Beecham, USA), Levormeloxiphene (3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7- methoxychroman) (Novo Nordisk, A / S / Denmark), disclosed by Shalmi et al., WO 97/25034, WO 97/25035, WO 97/25037, WO 97/25038; and Korsgaard et al WO 97/25036 ), GW5638 (described by Willson et al., Endocrinology, 138 (9), 3901-3911,1997) and indole derivatives (disclosed by Miller et al., EP 0802183A1) and TSE 424 developed by Wyeth Ayers (USA) and disclosed in JP 10036347 (American Home Products Corporation) and derivatives The non-steroidal estrogens described in WO 97/32837. Any SERM can be used as required for performance as recommended by the manufacturer. Appropriate dosages are known in the art. Any other commercially available non-steroidal anti-estrogen may be used. Any compound having a SERM-like activity can be used (example: Raloxifene). SERMs are preferably administered in a dose range of 0.01 to 10 mg / kg body weight per day (preferably 0.05 to 1.0 mg / kg), preferably 5 mg per day, especially 10 mg per day, in two equally divided doses for a person with an average body weight of Ia when administered orally or in the dose range of 0.003 to 3.0 mg / kg body weight Ia per day (preferably 0.015 to 0.3 mg / ml), preferably 1.5 mg per day, especially 3.0 mg per day, in two equally divided doses for an average person of body weight Ia by parenteral administration (i.e. is dominant, subcutaneous or transdermal). Preferably, the SERMs are administered together with a pharmaceutically acceptable diluent or carrier, as described below. Preferred bisphosphonates include Alendronate [(4-amino-1-hydroxybutylidene) bisphosphonic acid, disodium salt, hydrate] available from Merck Shape and Dohme under the trade name Fosamax, Etidronate [(1-hydroxyethylidene) bisphosphonic acid, 2 , 2'-iminobisethanol] available from Procter and Gamble under the trade names Didrocal and Didronel, Clodronate [(dichloromethylene) bisphosphonic acid, disodium salt] available from Rhöne-Poulenc Rorer under the trade name Bonefos or from Boehringer Mannheim under the trade name Ostac and Pamidronate (3-amino-1-hydroxypropylidene) bisphosphonic acid, disodium salt) available from Geigy under the trade name Aredia. Risedronate (1-hydroxy-2- (3-pyridinyl) ethylidene bisphosphonic acid, monosodium salt) is in clinical trials. Any other commercially available bisphosphonates can be used at the dosage recommended by the manufacturer. Likewise, it is possible to use sex steroid precursors in dosages recommended in the art, preferably in dosages that reproduce the levels in circulation to those of healthy 20-30 year old men or premenopausal adult women. With respect to all of the dosages recommended in the invention, the attending physician should monitor the response of the individual patient and adjust the dosage accordingly. Example 1 Substances and methodology Animal Female Sprague-Dawley rats [Crl: CD (SD) Br] were obtained at 44-46 days of age from Charles River Canada Inc. (St. Constant, Quebec) and kept 2 per cage under light (12 hours light / day; joined at 07:15) and in a temperature controlled environment (22 ± 2 ° C). The animals were fed Purina rodent food and tap water ad libitum. Animal studies were conducted in facilities approved by the Canadian Council on Animal Care (CCAQ) in accordance with the CCAC Guide for Care and Use of Experimental Anlmals. Induction of mammary tumors by DMBA Breast cancers were induced by a single intestinal administration of 20 mg DM-BA (Sigma Chemical Co., St. Louis, MO) in 1 ml corn oil at 50-52 days of age. Two months later, tumor measurements were taken every two weeks. The two largest perpendicular diameters of each tumor were recorded with calipers to assess tumor size as described (Asselin et al., Endocrinology 101: 666-671, 1977). The site, size and number of tumors were recorded. The eta animal therapy was randomized into groups, each containing 20 rats, except for 40 animals in the control group. The animal was treated for 282 days with the following: (1) control vehicles for DHEA and EM-800; (2) EM-800 ((+) - 7-pivaloyloxy-3- (4'-pivaloyloxyphenyl) -4-methyl-2- (4 "- (2" - piperidineethoxy) phenyl) -2H-benzopitran) ( 75 µg, orally, once daily) in 0.5 ml of 4% ethanol, 4% poly (ethylene glycol) -600, 1% gelatin, 0.9% NaCl suspension; (3) DHEA (10 mg, transdermal, once daily) in 0.5 mL and 50% ethanol, 50% propylene glycol; and (4) EM-800 and DHEA. Eto therapy should be started 3 days before the oral administration of DMBA. EM-800 was synthesized from the Medical Chemistry Department of our laboratory, from DHEA was purchased from Steraloids Inc., Wilton, NH. Many control animals and some EM-800 or DHEA treated animals were killed by cervical displacement under isoflurane anesthesia 6 months after administration of DMBA due to oversize tumors. The values of the size of the tumors and the number of these killed rats, along with those measured at later periods in living animals, were used for a later analysis of the incidence of tumors, the average number of tumors per tumor bearing rat, and the average tumor size in the animal bearing tumors. . The remaining animals (9 control rats and 13-19 rats from each of the other groups) continued to be treated for a further 3 months in order to observe the long-term preventive power of DHEA and EM-800 alone or in combination. The rats were sacrificed 279 days after dosing with DM-BA. Uteri, vaginas and ovaries were immediately removed from connective and fatty tissue and weighed. EN 203 438 B1 16 Sample Collection and Processing 24-hour urine samples were collected at the end of the experiment from the first 9 rats of each group after transfer to metabolic cages (Allentown Caging Equipment Co., Allentown, NJ). Two urine samples were collected and analyzed on different days for each animal to minimize the effect of daily variation. Thus, each value shown represents the average of two measurements taken on two different days. 0.5 ml of toluene was added to the urine tubes to prevent evaporation of urine, and bacterial growth and urine ethos were recorded. Trunk blood was collected after sacrifice and allowed to clot at 4 ° C overnight before centrifugation at 3000 rpm for 30 minutes. Analysis of Urine and Plasma Biochemical Parameters Fresh samples were used to test urine creatinine, calcium, and phosphorus levels, as well as plasma levels of total alkaline phosphatase (tALP), cholesterol, and triglycerides. These biochemical parameters were measured automatically on a Monarch 2000 Chemistry System (Instrumentation Laboratory Co. Lexington, MA) under Good Laboratory Practice conditions. Hydroxyproline e in urine was measured as described (Podenphant et al., Clinica Chimica Acta 142: 145-148, 1984). Bone weight measurements Rats were anesthetized with an intraperitoneal injection of ketamine hydrochloride and diazepam at doses of 50 and 4 mg / kg body weight Ia, respectively. The entire leg and right femur were scanned using dual energy x-ray absorptiometry (DEXA; QDR 2000-7.10C, Hologic, Waltham, MA) on an instrument equipped with Regional High Resolution software. The scanned fields were 28.110 x 17.805 cm and 5.0 x 1.902 cm, the resolution is 0.1511 x 0.0761 cm and 0.0254 x 0.0127 cm, the scanning speed is 0.3608 and 0.0956 respectively mm / s for the entire femur and femur. The bone mineral content (BMC) and the bone mineral density (BMD) of the whole bone, the vertebrae of the ligament and the femur were measured on the scanned images of the entire femur and femur. Statistical analyzes Statistical significance was measured according to the Duncan-Kramer multi-range test (Biometrics 12: 307-310, 1956). Analyzes of the frequency of the development of breast tumors were performed using the Fisher's exact test (Conover, Practical nonparametric statistics, 2nd edition, 153-170, 1980). Data are presented as means ± S.E.M. Results Effect of development of DMBA-induced breast cancer As shown in Figure 1, 95% of control animals developed palpable breast tumors 29 days after DMBA treatment. Treatment with DHEA or EM-800 partially prevented the development of DM-BA-induced breast cancer and the incidence was thus reduced to 57% (p <0.01) and 38% (p <0.01). Interestingly, the combination of both compounds resulted in a significantly higher inhibitory effect than that obtained by each compound alone (p <0.01 versus DHEA or EM-800 alone). In fact, the only two tumors that appeared in the group of animals treated with both compounds disappeared before the end of the experiment. DHEA or EM-800 therapy reduced the mean number of tumors in tumor bearing animals from 4.7 ± 0.5 tumors in control animals to 3.4 ± 0.7 (NS) and 1.4 ± 0, respectively , 3 (p <0.01) tumors / animals, while no tumor was found at the end of the experiment in animals that had received both drugs (p <0.01 versus three other groups) (Fig. 2A). One of the two tumors that disappeared later was present from day 79 to day 201 after DM-BA administration and the other tumor was palpable from day 176 to day 257. You can see from Figure 2B that DHEA or EM alone was -800 reduce the mean tumor area in the animal with tumors from 12.8 ± 1.3 cm 2 at the end of the experiment to 10.2 ± 2.1 cm 2 (NS) and 7.7 ± 1.8 cm 2, respectively (NS), while combination therapy gave a sc value of zero (see <0.01 versus three other groups). Two tumors developed in the group of animals treated with DHEA and with EM-800 did not grow larger than 1 cm 2. It should be noted that the actual mean tumor area values as well as the mean number of tumors per tumor bearing animal in the control group should be higher than the values shown in Fig. 2 because many rats would need to be I had killed before the end of the experiment due to the excessive size of the tumors. The values measured at the time of kill were therefore included as such in the calculations of n made later to minimize the trend in the control group, which in any case remained significantly above the other groups. PL 203 438 B1 17 Wp on bone Long-term percutaneous administration of DHEA to female rats induced 6.9% (p <0.01), 10.6% (p <0.05), and 8.2% (p <0.01) increases in bone mineral density (BMD) of the entire femoral vertebrae, lumbar vertebrae and femur (Table 2). On the other hand, no significant changes were found in the animals treated with EM-800. Moreover, when | both compounds were administered simultaneously, the obtained values were comparable with those obtained with DHEA alone. DHEA therapy increased plasma levels of total alkaline phosphatase (tALP) activity by 74% (p <0.05) but had no effect on the daily urinary excretion of calcium and phosphorus and the urinary hydroxyproline to creatinine ratio (Table 3). On the other hand, treatment with EM-800 will reduce the urinary hydroxyproline to creatinine ratio by 48% (p <0.01), but had no statistically significant effect on daily urinary calcium or phosphorus excretion and plasma tALP levels. The combination of DHEA and EM-800 led to an increase in the levels of plasma tALP activity (see <0.01) | similar to those obtained with DHEA alone and reduced the ratio of hydroxyproline to creatinine in urine by 69%, the values are significantly (p <0.01) lower than that obtained with the EM-800 alone. In addition, the combination of both drugs significantly reduced the daily excretion of calcium and phosphorus in the urine by 84% (p <0.01) and 56% (p <0.01), while no significant change was observed for each drug alone (Table 3). Effect on plasma lipid levelsD long-term treatment with EM-800 lowers plasma levels of triglycerides and cholesterol by 72%, respectively (p <0.01) and 45% (p <0.01), while long-term administration of DHEA reduced plasma triglyceride levels by 60% (p <0.01) and blood cholesterol levels did not change. Moreover, 42% (p <0.01) and 52% (p <0.01), decreases in plasma triglycerides and cholesterol concentrations were measured in animals treated with EM-800 and DHEA (Fig. 3). Table 2 Effect of treatment with DHEA (10 mg, transdermal, once daily) or EM-800 (75 µg, orally, once daily) alone or in combination for 9 months on bone mineral density (BMD) the femoral vertebrae, and the entire calf in female rats. The measurements were carried out for 9 rats in the group e G esto sc mineral bone (g / cm 2) Group Total end Femoral calves Femoral bones Control 0.1371 ± 0.0025 0.195 ± 0.0067 0.3151 ± 0.0063 DHEA (10 mg) 0.1465 ± 0.0010 ** 0.2161 ± 0.0049 * 0.3408 ± 0.0038 ** EM-800 (75 µg) 0.1356 ± 0.0017 0, 1885 ± 0.0045 0.3097 ± 0.0047 DHEA + EM-800 0.1498 ± 0.0019 ** 0.210 ± 0.0061 0.3412 ± 0.0056 ** *: p <0.05; **: p <0.01, experiment versus control Table 3 Effect of treatment with DHEA (10 mg, transdermal, once daily) or EM-800 (75 µg, orally, once daily) alone or in combination for 9 months on parameters of co-metabolism Rat biopsy: Daily urinary calcium and phosphorus excretion, urinary hydroxyproline to creatinine ratio (HP / Cr), and plasma total alkaline phosphatase (tALP) levels. Samples were obtained for 9 animals in the group Urine Plasma Wap group n (µmol / / 24 h / 100 g) Phosphorus (µmol / / 24 h / 100 g) HP / Cr (µmol / mmol) tALP (IU / 1) Control 23 , 17 ± 1.55 132.72 ± 6.08 13.04 ± 2.19 114.25 ± 14.04 DHEA (10 mg) 25.87 ± 3.54 151.41 ± 14.57 14.02 ± 1.59 198.38 ± 30.76 * EM-800 (75 fig) 17.44 ± 4.5 102.03 ± 25.13 6.81 ± 0.84 ** 114.11 ± 11.26 DHEA + EM-800 3.71 ± 0.75 ** 59.06 ± 4.76 ** 4.06 ± 0.28 ** 204.38 ± 14.20 ** *: p <0.05; **: p <0.01 experiment versus control PL 203 438 B1 18 P r y k l a d 2 Summary In the mammary gland, androgens are formed from the precursor of the steroid dehydroepiandrosterone (DHEA). Clinical evidence shows that androgens have an inhibitory effect on breast cancer. Estrogens, on the other hand, stimulate the development and growth of breast cancer. They tested the effect of DHEA alone or in combination with the newly described pure antiestrogen, EM-800, on the growth of tumor xenografts formed by the ZR-75-1 human breast cancer cell line in ovariectomized nude mice. Mice received a daily subcutaneous injection of 0.5 µg of estrone (an estrogenic hormone) immediately after ovariectomy. EM-800 (15, 50 or 100 µg) was administered orally once daily. DHEA was administered twice daily (total dose 0.3, 1.0 or 3.0 mg) on the dorsal skin alone or in combination with a 15 µg daily oral dose of EM-800. Changes in tumor size in response to treatment were assessed periodically with respect to the measurements on the first day. At the end of the experiments, the tumors were removed and weighed. A 9.4-fold increase in tumor size over 9.5 months was observed in ovariectomized mice receiving estrone alone compared to mice not receiving estrone. Administration of 15, 50 or 100 µg of EM-800 to estrone-treated mice in ovariectomized mice resulted in inhibition of 88%, 93% and 94% of tumor sizes, respectively. DHEA, on the other hand, at doses of 0.3, 1.0 or 3.0 mg inhibited the end tumor mass by 67%, 82% and 85%, respectively. Comparable inhibition of tumor size was obtained with a daily 15 µg oral dose of EM-800 in the presence or absence of various doses of percutaneous DHEA. DHEA and EM-800 independently suppressed the growth of estrone-stimulated mouse xenograft ZR-75-1 tumors in nude mice. Administration of DHEA in defined doses does not change the inhibitory effect of EM-800. Material and methodology ZR-75-1 cells ZR-75-1 human breast cancer cells were obtained from the American Type Culture Collection (Rockville, MD) and routinely grown as monolayers in RPMl 1640 medium supplemented with 2 mM L-glutamine, 1 mM pyruvate sodium, 100 IU penicillin / ml, 100 µg streptomycin / ml and 10% p ice bovine serum in a humid atmosphere of 95% air / 5% CO 2 at 37 ° C as described (Poulin and Labri, Cancer Res. 46 : 4933-4937, 1986; Poulin et al., Breast Caiticer Res. Treat., 12: 213-225, 1988). Cells were streaked every week after treatment with 0.05% trypsin a: 0.02% EDTA (weight). The bacterial cultures used in the experiments described in this report were obtained from lane 93 of the ZR-75-1 cell line. Female homozygous Harian Sprague-Dawley (nu / nu) athymic mice (28 to 42 days old) were obtained from HSD (Indianapolis, Indiana, USA). Mice were housed in vinyl cages with a roof air filter in hoods with laminar airflow and under pathogen limited conditions. Cages, bedding, and food were autoclaved prior to use. The water was autoclaved, acidified to pH 2.8 and added freely. Cell vaccination Mice have both ovaries excised (OVX) one week prior to tumor cell inoculation under intraperitoneal anesthesia and 0.25 ml injection / animal Avertin (amyl alcohol: 0.8 g / 100 ml 0.9% NaCl and tribromoethanol: 2 g / 100 ml 0.9% NaCl). 1.5 x 10 10 ZR-75-1 cells in log phase growth were harvested after treatment with 0.05% trypsin / 0.02% EDTA monolayer (by weight), resuspended in 0.1 ml of culture medium containing 25% Matrigel and inoculated with subcutaneously on both sides of the animals using a # 20 syringe and a 1 inch needle as previously described (Dauvois et al., Cancer Res. 51: 3131-3135, 1991). In order to facilitate tumor growth, each animal was given a daily subcutaneous injection of 10 µg estradiol (E 2) in a vehicle mixed with 0.9% NaCl, 5% ethanol, 1% gelatin for 5 weeks. After the appearance of palpable ZR-75-1 tumors, the tumor diameter was measured with calipers and mice having a tumor diameter between 0.2 and 0.7 cm were selected for this study. Hormone therapy All animals, except those in the OVX control group, received daily subcutaneous injections of 0.5 µg of estrone (E 1) in 0.2 ml of 0.9% NaCl, 5% ethanol, 1% gelatin. In the indicated groups, DHEA was administered percutaneously twice daily at doses of 0.3, 1.0 or 3.0 mg / animal in a volume of 0.02 ml on the dorsal skin beyond the surface of the tumor growth. DHEA was dissolved in 50% ethanol, 50% propylene glycol. EM-800, ((+) - 7-pivaloyloxy-3- (4'-pivaloyloxyphenyl) -4-methyl-2- - (4 "- (2" '- piperidineethoxy) phenyl) -2H-benzopyran), synthesized as described previously (Gauthier et al., J. Med. Chem. 40: 2117-2122, 1997) in the medical chemistry department of the Laboratory of Molecular Endocrinology CHUL Research Center. EM-800 was dissolved in 4% (ethical v / v) ethanol, 4% (ethical v / v) poly (ethylene glycol) (PEG) 600, 1% (w / w) gelatin, 0.9% (w / w) NaCl. Animals of the indicated groups received daily oral doses of 15 μg, 50 μg or 100 μg of EM-800 alone or in combination with DHEA, while animals from the OVX group received the carrier alone (0.2 ml, 4% ethanol, 4% PEG 600, 1% Gelatin, 0.9% NaCl Tumors were measured once a week with a Vernier caliper Diameters perpendicular in cm (L and W) were recorded and tumor area (cm 2) was calculated using the formula: L / 2 x W / 2 xp (Dauvois et al., Cancer Res. 51: 3131-3135, 1991) The area measured on the first day of treatment was taken as 100% and changes in tumor size were expressed as a percentage of the initial tumor area. tumors are generally not (accurate three-dimensional access to the tumor possible, so only tumor areas were measured. After 291 days (or 9.5 months) of treatment, animals were killed. Response categories were assessed as described (Dauvois and et al., Breast Cancer Res. Treat. 14: 299-306, 1989; Dauvois et al., Eur. J. Cancer Clin. Oncol. 25: 891-897, 1989; Labrie et al., Breast Cancer Res. Treat. 33: 237 -244,1995). Briefly, partial regression corresponds to tumors that shrunk by 50% or more than 50% of their original size; The permanent answer is for tumors that shrunk by less than 50% of their original size or enlarged by less than 50% of their original size, while complete regression is for tumors that they were undetectable at the end of treatment. Progression refers to tumors that have enlarged by more than 50% compared to their initial size. At the end of the experiment, all animals were killed by cutting their heads. Tumors, uterus and vagina were removed immediately, freed of connective and fatty tissue and weighed. Statistical analysis The statistical significance of the effect of treatment on tumor size was assessed using the analysis of variance (ANOVA) assessing the effects related to DHEA, EM-800 and time and re-measurements in the same animals were performed at the beginning and at at the end of therapy (subjects in the factor group). Repeated measurements during 0 and 9.5 months of treatment constituted a stochastic block of animals. Time was therefore analyzed as intra-block effect, while both treatments were assessed as inter-block effects. All interactions between the main effects are linked to the model. The importance of therapy factors and their interactions was analyzed by using individuals in the group as error factor. Data was log transformed. The hypotheses underlying the ANOVA assumed normal residuals and homogeneity of variance. A posteriori pairwise comparisons were made using the Fisher test for the least significant difference. The main effects and interactions of therapy on body mass and organ mass were analyzed using a standard two-way interaction ANOVA. All ANOVA analyzes were performed using the SAS program (SAS Institute, Cary, NC, USA). The significance of the differences was declared using a two-sided test with a total level of 5%. Data in terms of the Kruskall-Wallis test for structured categorical response variables (complete response, partial response, ongoing response and tumor progression). After an overall evaluation of the treatment outcomes, the subgroups of outcomes presented in Table 4 were analyzed by setting the critical p-value for multiple comparisons of n. Exact p-values were calculated using the StatXactp program (Cytel, Cambridge, MA, USA). Data are expressed as the mean standard error of the mean (SEM) of 12 to 15 mice in each group. Results As shown in Figure 4A, human ZR-75-1 tumors increased 9.4 fold over 291 days (9.5 months) in ovariectomized nude mice treated daily with 0.5 µg s.c. The administered estrone dose, while in the control OVX mice that received the carrier alone, the tumor size decreased to 36.9% of the initial value during the course of the study. Therapy with increasing doses of percutaneous DHEA caused a progressive inhibition of E1-stimulated ZR-75-1 tumor growth. Inhibitions of 50.4%, 76.8% and 80.0% of the achievement of eto over 9.5 months of treatment with 0.3 mg, 1.0 mg and 3.0 mg daily doses of DHEA per animal, respectively (Fig. 4A). In line with the decrease in total tumor burden, DHEA treatment led to a significant decrease in the mean weight of tumors remaining at the end of the experiment. In fact, the mean tumor weight decreased from 1.12 ± 0.26 g. controls of E 1-treated nude mice ovariectomized to 0.37 ± 0.12 g (P = 0.005), 0.20 ± 0.06 g (P = 0.001) and 0.17 ± 0.06 g, respectively (P = 0.0009) in the group of animals receiving 0.3, 1.0 and 3.0 mg daily doses of DHEA (Fig. 4B). At daily doses of 15 µg, 50 µg and 100 µg, the antiestrogen EM-800 inhibits estrogen-stimulated tumor sizes by 87.5% (P <0.0001), 9.5% (P <0.0001) and 94.0% (P = 0.0003) (Fig. 5A) compared with tumor sizes in control animals at 9.5 months. The tumor size reductions obtained with the three doses of EM-800 did not differ significantly between each other. As illustrated in Fig. 4B, the tumor mass at the end of the 9.5-month study decreased from 1 , 12 ± 0.26 g in control E1-treated OVX mice to 0.08 ± 0.03 g, 0.03 ± 0.01 g and 0.04 ± 0.03 g in animals treated daily with 15 µg, 50 µg and 100 µg with doses of EM-800, respectively (P <0.0001 at all doses of EM-800 versus treated with E 1 OVX). As mentioned above, the antiestrogen EM-800, at a daily oral dose of 15 µg, caused 87.5% inhibition of estrone-stimulated tumor growth measured at 9.5 months. The addition of DHEA at the three doses used had no significant effect on the already significant inhibition of tumor size obtained with the 15 µg daily dose of the antiestrogen EM-800 (Fig. 5B). Thus, the mean tumor weight was strongly reduced from 1.12 ± 0.26 g in control estrone-treated mice to 0.08 ± 0.03 g (P <0001), 0.11 ± 0.04 g (P = 0.0002), 0.13 ± 0.07 g (P = 0.004) and 0.08 ± 0.05 g (P <0001) in animals that received a daily dose of 15 μg of antiestrogen alone or in combination with 0.3, 1.0, and 3.0 mg doses of DHEA, respectively (no significant difference was noticed between 4 groups) (Fig. 4B). It was also interesting to examine the categories of responses obtained with the above-mentioned therapies. Thus, treatment with increasing doses of DHEA reduced the number of growing tumors, although not to the level of statistical significance (P = 0.088), from 87.5% in control OVX animals treated with oestrone to 50 , 0%, 53.3% and 66.7% in animals treated with daily doses of 0.3, 1.0, or 3.0 mg of DHEA (Table 4). Complete responses, on the other hand, increased from 0% in estrone-treated mice to 28.6%, 26.7%, and 20.0% in animals maintaining 0.3, 1.0, and 3.0 mg daily percutaneous dose of DHEA. Permanent responses, on the other hand, were measured at 12.5%, 21.4%, 20.0%, and 13.3% in the control treated mice and in the three groups of animals that received the above-indicated doses, respectively. DHEA. In control ovariectomized mice, the sizes of complete, partial and permanent responses were measured at 68.8%, 6.2% and 18.8%, respectively, while progression was seen in only 6.2% of the tumors. (table 4). Complete responses or disappearance of tumors were obtained for 29.4%, 33.3%, 26.7%, and 35.3% of tumors in animals that received andestrogen EM-800 alone (P = 0.0006) (15 μg ) or in combination with 0.3 mg, 1.0 mg or 3.0 mg DHEA, respectively (table 4). Progression, on the other hand, was observed for 35.3%, 44.4%, 53.3% and 17.6% of the tumors in the same group of animals, respectively. There is no significant difference between groups treated with EM-800, alone or in combination with DHEA. There was no significant effect of DHEA or EM-800 therapy on body mass, including tumor mass. Treatment of OVX mice with estrone increased uterine weight from 28 ± 5 mg in control OVX mice to 132 ± 8 mg (P <0.01), while increasing the doses of DHEA resulted in a progressive but relatively little inhibition of the stimulatory effect of estrone, which reached al 26% (P = 0.0008) at the highest used a dose of DHEA. It can be seen from the same figure that the weight of the estrone stimulated uterus decreased from 132 ± 8 mg in the control estrone-treated mice to 49 ± 3 mg, 36 ± 2 mg and 32 ± 1 mg (P <0.0001 at all doses relative to controls) with daily oral doses of 15 µg, 50 µg or 100 µg respectively EM-800 (including P <0,0001). 15 µg of EM-800 in combination with 0.3 mg, 1.0 mg or 3.0 mg of the daily dose of DHEA gave the measured uterine weight of 46 ± 3 mg, 59 ± 5 mg and 69 ± 3 mg, respectively. On the other hand, estrone therapy increases the vaginal weight from 14 ± 2 mg in OVX animals to 31 ± 2 mg (P <0.01), while the addition of DHEA had no significant effect. The vaginal weight then decreases to 23 ± 1 mg, 15 ± 1 mg and 11 ± 1 mg after daily therapy with 15 µg, 50 µg or 100 µg doses of EM-800, respectively (total p and P <0.0001 for couples at all doses versus controls) PL 203 438 B1 21 In combination with the 0.3 mg, 1.0 mg or 3.0 mg doses of DHEA and EM-800, vaginal weights were measured by receiving 22 ± 1 mg, 25 ± 2 mg and 23 ± 1 mg (NS for all groups relative to 15 µg EM-800). It should be noted that at the highest dose used, 100 µg / day, EM-800 reduced the uterine weight in estrone-treated OVX animals to a value not different from the control OVX value, while vaginitis decreased to a value below that measured for the control OVX animals (P <0.05). DHEA, presumably due to its androgenic effects, partially combats the effect of EM-800 on uterine and vaginal weight. Table 4 Effect of percutaneous administration of DHEA or oral administration of EM-800 alone or in combination for 9.5 months on responses (complete, partial, persistent and progression) of human breast tumor xenografts ZR-75- 1 in nude mice Response category Complete Partial Continuous Progression Group Total number of animals Number i% OVX 16 11 (68.8) 1 (6.2) 3 (18.8) 1 (6.2) OVX + E 1 (0.5 µg) 16 0 (0) 0 (0) 2 (12.5) 14 (87.5) OVX + E 1 (0.5 µg) + DHEA 0.3 mg 1.0 mg 3, 0 mg 14 15 15 4 (28.6) 4 (26.7) 3 (20.0) 0 (0) 0 (0) 0 (0) 3 (21.4) 3 (20.0) 2 (13 , 3) 7 (50.0) 8 (53.3) 10 (66.7) OVX + E 1 (0.5 µg) + EM-800 15 mg 50 mg 100 mg 17 16 16 5 (29.4) 4 (25.0) 8 (50.0) 1 (5.9) 3 (18.8) 0 (0) 5 (29.4) 5 (31.2) 3 (18.8) 6 (35, 3) 4 (25.0) 5 (31.2) OVX + E 1 (0.5 µg) + EM-800 + DHEA 0.3 mg 1.0 mg 3.0 mg 18 15 17 6 (33.3 ) 4 (26.7) 6 (35.3) 0 (0) 0 (0) 0 (0) 4 (22.2) 3 (20.0) 8 (47.1) 8 (44.4) 8 (53.3) 3 (17.6) E 1 = estrone; DHEA = Dehydroepiandrosterone; OVX = ovariectomized Example 3 Animal eta and treatment Female Sprague-Dawley rats aged 50 to 60 days (Crl: CD (SD) Br) (Charles River Laboratory, St-Constant, Canada) were used. 190 g during the ovariectomy. The animal was accustomed to the environmental conditions (temperature: 22 ± 3 ° C; humidity: 50 ± 20%; cycles of 12 hours of light - 12 hours of the night, switching on the light at 07:15) for 1 week before the procedure . The animals were kept three per cage and had free access to tap water and certified pelleted rodent food (Lab Diet 5002, Ralston Purina, St-Louis, MO). The experiment was conducted in a facility approved by the Canadian Council on Animal Care in accordance with the CCAC Guide for Care and Use of Experimental Animals. Ovariectomy from 136 female rats under isoflurane anesthesia on day 0 of the study, and randomized them into 17 groups of animals for the study explained below: Group 1: OVX Control Group 2: OVX + EM-800 (0.01 mg / kg, orally, ID) Group 3: OVX + EM-800 (0.03 mg / kg, orally, ID) Group 4: OVX + EM-800 (0.1 mg / kg, orally, ID) Group 5 : OVX + EM-800 (0.3 mg / kg, orally, ID) Group 6: OVX + EM-800 (1 mg / kg, orally, ID) Group 7: OVX + EM-01538 (0.01 mg / kg, orally, ID) Group 8: OVX + EM-01538 (0.03 mg / kg, orally, ID) PL 203 438 B1 22 Group 9: OVX + EM-01538 (0.1 mg / kg, orally, ID ) Group 10: OVX + EM-01538 (0.3 mg / kg, orally, ID) Group 11: OVX + EM-01538 (1 mg / kg, orally, ID) Group 12: OVX + Raloxifene EM-1105 (0 , 01 mg / kg, orally, ID) Group 13: OVX + Raloxifene EM-1105 (0.03 mg / kg, orally, ID) Group 14: OVX + Raloxifene EM-1105 (0.1 mg / kg, orally, ID) Group 15: OVX + Raloxifene EM-1105 (0.3 mg / kg, orally, ID) Group 16: OVX + Raloxifene EM-1105 ( 1 mg / kg, orally, ID) Group 17: INT Control Drug administration was started on study day 10 and was administered orally with a spike daily until study day 13. Dosing suspensions were made in 0.4% methylcellulose and the concentration was adjusted according to the group average Ia weight recorded on the day of testing to produce 0.5 ml of dosing suspension per rat. Approximately 24 hours after the last dosing, the overnight fasted animal was killed by abdominal artery bleeding under isoflurane anesthesia, and blood samples were processed to produce plasma. The uteri were removed from the eto, cleared of residual fat and weighed. Plasma cholesterol and triglyceride test Total plasma cholesterol and triglyceride levels were determined using the Boehringer Mannheim Diagnostic Laboratory Systems. Example 4 Androstene-3 ß, 17 ß-diol (5-diol) has an internal estrogenic activity. Moreover, as a precursor to sex steroids, it can be converted into active androgens and / or other estrogens in the peripheral secretory tissues. To test the relative importance of the androgenic and estrogenic components of the action of 5-diol on bone mass, 21-week-old rats were ovariectomized and treated percutaneously once daily with 2, 5 or 12.5 mg of 5-diol alone. or in combination with the anti-androgen Flutamide (FLU, 10 mg sc, once daily) and / or the anti-estrogen EM-800 (100 µg, sc once daily) for 12 months. The bone mineral density (BMD) was measured after 11 months of treatment. Ovarian discharge (OVX) led to a 12.8% decrease in femoral BMD (see <0.01), while treatment with the highest dose of 5-diol will restore 34.3% of femoral BMD lost during 11 months after OVX (p <0.01). Co-administration of FLU completely prevented the stimulatory effect of 5-diol on femoral BMD, while the addition of EM-800 resulted in an additional 28.4% stimulation compared to the effect of 5-diol alone. Co-administration of 5-diol, FLU and EM-800 only showed an effect of EM-800 (27%), as the effect of 5-diol was completely blocked by FLU. Comparable results were obtained for the BMD of the ledal vertebrae, although with BMD of the ledal vertebrae in OVX rats receiving 12.5 mg of 5-diol alone, 12.5 mg of 5-diol + EM-800 or 5-diol + FLU + EM-800 returned to the values not significantly different from those for non-affected animals. Histomorphometric analysis shows that the stimulating effects of 5-diol on bone volume, beam number and inhibitory effect on trabecular separation in secondary trabecular densities in the near baseline area are inhibited by FLU, but in turn enhanced by the EM-800. Significant stimulation of the plasma alkaline phosphatase activity level obtained after treatment with 5-diol is 57% (p <0.01 versus 12.5 mg 5-diol alone) and is reversed by simultaneous administration of FLU. Treatment with 5-diol had no statistically significant inhibitory effect on the urinary calcium / creatinine ratio. The highest dose of 5-diol caused a significant 23% (p <0.01) decrease in plasma cholesterol, while the addition of EM-800 decreased plasma cholesterol by 62% (p <0.01). The present data clearly show the stimulating effect of 5-diol on bone formation and suggest that while 5-diol is a poor estrogen, its stimulating effect on bone formation is mainly mediated by the effect androgenic. Moreover, the additional stimulatory effects of EM-800 and 5-diol on bone mass show the bone-sparing effect of the antiestrogen EM-800 in rats. The cholesterol-lowering activity of 5-diol and EM-800 may have an interesting application in the prevention of cardiovascular disease. PL 203 438 B1 23 Example 5 Alkaline group of phosphatase in plasma OH-proline / creatinine in urine LH Levels of mRNA GnRH Cholesterol Triglycerides IU / l µmol / mmol ng / ml silver grains per cell mmol / l mmol / l Uninfected control 30 ± 3 ** 15.4 ± 1.3 0.09 ± 0.03 ** 33.7 ± 0.7 ** 2.28 ± 0.12 1.4 ± 0.2 OVX Control 51 ± 4 11.7 ± 1.2 3.55 ± 0.50 44.0 ± 0.9 2.29 ± 0.16 1.1 ± 0.1 OVX + MPA 57 ± 4 11.7 ± 1.2 2.51 ± 0.20 * 35.5 ± 0.7 ** 2.55 ± 0.14 1.3 ± 0.1 OVX + E 2 41 ± 5 9.2 ± 0.9 2.37 ± 0.45 * 40.4 ± 0.8 ** 2.02 ± 0.15 0.8 ± 0.1 OVX + DHT 56 ± 5 7.8 ± 0.7 * 1.55 ± 0.27 ** 38.8 ± 0.7 ** 2.44 ± 0.16 0.9 ± 0.1 OVX + DHEA 201 ± 25 ** 7.3 ± 1.0 * 0.02 ± 0.01 ** 34.5 ± 0.7 ** 1.78 ± 0.16 * 0.8 ± 0.1 OVX + DHEA + FLU 103 ± 10 ** 14.5 ± 1.2 1.13 ± 0.24 ** 41.5 ± 0.7 * 2.27 ± 0.15 0.8 ± 0.1 OVX + DHEA + EM-800 202 ± 17 ** 6.4 ± 1.0 ** LD ** 39.2 ± 0.7 ** 0.63 ± 0.09 ** 1.0 ± 0, 2 LD: Detection limits: 0.01 ng / ml * p <0.05; ** p <0.01 relative to OVX control Example 6 Example of the synthesis of a preferred compound according to the invention Synthesis of (S) - (+) - 7-hydroxy-3- (4'hydrocyphenyl) -4-methyl-2- (4) hydrochloride "- (2" '- piperidine-ethoxyphenyl) -2H-1-benzopyran, EM-01538 (EM-652, HCl) PL 203 438 B1 24 Step A: BF 3 Et 2 O, toluene; 100 ° C; 1 1 hour Step C: 3,4-dihydropyran, p-toluenesulfonic acid monohydrate, ethyl acetate; 25 ° C under nitrogen, 16 hours followed by crystallization in isopropanol Steps D, E and F: (1) piperidine, toluene, Dean and Stark apparatus, reflux under nitrogen; (2) 1,8-diazabicyclo [5.4.0] udndec-7-ene, DMF, reflux 3 hours; (3) CH 3 MgCl, THF, -20 to 0 ° C and then room temperature for 24 hours; Steps G, H: (1S) - (+) - 10-camphorsulfonic acid, acetone, water, toluene, room temperature, 48 hours. Step HH: 95% ethanol, 70 ° C, then room temperature 3 days HHR step: Recycle the mother liquor and wash from HH step (1S) -10-camphorsulfonic acid, reflux; 36 hours then tempe room temperature for 16 hours. Step I: (1) Aqueous DMF, Na 2 CO 3, ethyl acetate; (2) ethanol, diluted with HCl; (3) water. Synthesis of 2-tetrahydropyranyloxyhydroxy-2 '- (4 "-tetrahydropyranyloxyphenyl) acetophenone (4) Suspension of 2,4-dihydroxy-2' - (4" -hydroxyphenyl) acetophenone 3 (97.6 g, 0.4 mol) (available epny from Chemsyn Science Laboratories, Lenexa, Kansas) in 3,4-dihydropyran (218 mL, 3.39 mol) and ethyl acetate (520 mL) were treated with p-toluenesulfonic acid monohydrate (0.03 g, 0.158 mmol) at a temperature of about 25 ° C. The reaction mixture was stirred under nitrogen without external heating for about 16 hours. The mixture was then washed with a solution of sodium hydrogen carbonate (1 g) and sodium chloride (5 g) in water (100 ml). The phases were separated and the organic phase was washed with brine (20 ml). Each sample was re-extracted with 50 mL of ethyl acetate. All organic phases were combined and filtered over sodium sulfate. Solvent (approximately 600 mL) would remove the etho by atmospheric distillation and isopropanol (250 mL) was added. Additional solvent (approximately 300 ml) was distilled under atmospheric pressure and isopropanol (250 ml) was added. Additional solvent (approximately 275 ml) was distilled under atmospheric pressure and isopropanol (250 ml) was added. The solution was cooled to approximately 25 ° C with stirring, and after approximately 12 hours, the crystalline solids were filtered off, washed with isopropanol and dried (116.5 g, 70%). Synthesis of 4-hydroxy-4-methyl-2- (4 '- [2 "-piperidine] ethoxy) phenyl-3- (4"' - tetrahydropyranyloxy) phenyl-7-tetrahydropyranyloxychroman (10) 2-tetrahydropyranyloxy-4 solution -hydroxy-2 '- (4 "-tetrahydropyranyloxyphenyl) acetophenone 4 (1 kg, 2.42 mol), 4- [2- (1-piperidino) ethoxy] benzaldehyde 5 (594 g, 2.55 mol) (available from Chemsyn Science Laboratories, Lenexa, Kansas) and piperidines (82.4 g, 0.97 moles) (available from Aldrich Chemical Company Inc., Milwaukee, Wis.) in toluene (8 L) were refluxed under nitrogen with an apparatus Dean and Stark to collect one equivalent of water (44 mL). Toluene (6.5 L) will remove etho from solution by atmospheric distillation. Dimethylformamide (6.5 L) and 1,8-diazabicyclo [5.4 L] are added. , 0] undec-7-ene (110.5 g, 0.726 mol) The solution was stirred for about 8 hours at room temperature to isomerize chalcone 8 to chromanon 9 and then added to an ice-water mixture (8 L) and toluene (4 L) The phases were separated and the toluene layers were washed with water (5 L). The combined aqueous slurry was extracted with toluene (3 x 4 L). The combined toluene extracts were finally washed with brine (3 x 4 L), concentrated at atmospheric pressure to 5.5 L and then cooled to -10 ° C. With continuous external cooling and stirring under nitrogen, a 3M solution of methylmagnesium chloride in THF (2.5 L, 7.5 mol) (available from Aldrich Chemical Company Inc., Milwaukee, Wis.) Was added while maintaining temperature below 0 ° C. After adding all of the Grignard reagent, the external cooling was removed and the mixture was allowed to warm to room temperature. The mixture was stirred at this temperature for approximately 24 hours. The mixture was re-cooled to about -20 ° C and with continuous external cooling and stirring, saturated ammonium chloride solution (200 ml) was added slowly keeping the temperature below 20 ° C. The mixture was stirred for 2 hours and then saturated ammonium chloride solution (2 L) and toluene (4 L) were added and stirred for 5 minutes. The phases were separated and the aqueous layer was extracted with toluene (2 x 4 L). The combined toluene extracts were washed with dilute hydrochloric acid until the solution became homogeneous and then brine (3 x 4 L). The toluene solution was finally concentrated at atmospheric pressure to 2 L. This solution was used directly in the next step. Synthesis of (1S) -10-camphorsulfonic acid salt (2R, S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4 "- [2" '- piperidine] ethoxy) phenyl ) -2H-1-benzopyran (± 12) To toluene solution 4-hydroxy-4-methyl-2- (4 '- [- 2 "-piperidine] ethoxy) -phenyl-3- (4'" - tetrahydropyranyloxy ) phenyl-7-tetrahydropyranyloxychroman (10), acetone (6 L), water (0.3 L) and (S) -10-camphorsulfonic acid (561 g, 2.42 mol) (available from Aldrich Chemical Company Inc ., Milwaukee, Wis.). The mixture was stirred under nitrogen for 48 hours, then the solid salt of (1S) -10-camphorsulfonic acid (2R, S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4 " - [2 "'- piperidino] ethoxy) phenyl) -2H-1-benzopyran (12) filtered, washed with acetone and dried (883 g). This material was used in the next (HH) step without further purification. Synthesis of (1S) -10-camphorsulfonic acid (2S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4 "- [2 '" - piperidino] ethoxy) phenyl salt) -2H-1-benzopyran (13, (+) - EM-652 (1S) -CSA salt) Suspension of (1S) -10-camphorsulfonic acid (2R, S) -7-hydroxy-3- (4'- hydroxyphenyl) -4-methyl-2- (4 "- [2 '" - piperidine] ethoxy) phenyl) -2H-benzopyran 12 (759 g) in 95% ethanol was heated with stirring to about 70 ° C, until lo was dissolved. The solution was allowed to cool to room temperature with stirring, then was seeded with several crystals of (1S) -10-camphorsulfonic acid (2S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2-salt. (4 "-phenyl) -2H-1-benzopyran 13. The solution was stirred at room temperature for a total of about three days. The crystals were filtered, washed with 95% ethanol and dried (291 g, 76%). The sc of the product is 94.2% and the purity is 98.8%. Synthesis of (S) - (+) - 7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4 "-) hydrochloride (2 '"- piperidine-ethoxy) phenyl) -2H-1-benzopyran, EM-01538 (EM-652, HCl) Suspension of compound 13 (EM-652 salt - (+) - CSA, 500 mg, 0.726 mmol ) in dimethylformamide (11 µl, 0.15 mmol) was treated with 0.5 M aqueous sodium eglate (7.0 ml, 3.6 mmol) and stirred for 15 minutes. The suspension was treated with ethyl acetate (7.0 ml) and stirred for 4 hours The organic phase was washed with an aqueous saturated sodium carbonate solution (2 x 5 ml) and brine (1 x 5 ml), dried over sulfate magnesium and concentrated. A solution of the resulting pink foam (EM-652) in ethanol (2 ml) was treated with 2N hydrochloric acid (400 µl, 0.80 mmol), stirred for 1 hour, treated with distilled water (5 ml) and stirred for 30 minutes. minutes. A slurry formed, filtered, washed with distilled water (5 mL), dried in air and in high vacuum (65 ° C) to afford 77%); fine white lava powder; scanning calorimetry: beginning of the melting peak at 219 ° C, ∆H = 83 J / g; [a] 24 D = 154 ° in methanol 10 mg / ml. 1 H NMR (300 MHz, CD 3 OD) d (ppm) 1.6 (broad, 2H, H-4 ""), 1.85 (broad, 4H, H-3 "" and 5 ""), 2 .03 (s, 3H, CH 3), 3.0 and 3.45 (broad, 4H, H-2 "" and 6 ""), 3.47 (t, J = 4.9 Hz, 2H, H -3 ""), 4.26 (t, J = 4.9 Hz, 2H, H-2 ""), 5.82 (s, 1H, H-2), 6.10 (d, J = 2 , 3 Hz, 1H, H-8), 6.35 (dd, J = 8.4, 2.43 Hz, 1H, H-6), 6.70 (d, J = 8.6 Hz, 2H, H-3 'and H-5'), 6.83 (d, J = 8.7 Hz, 2H, H-3 "and H-5"), 7.01 (d, J = 8.5 Hz, 2H, H-2 'and H-6'), 7.12 (d, J = 8.4 Hz, 1H, H-5), 7.24 (d, J = 8.6 Hz, 2H, H- 2 "and H-6"); 13 C RMN (CD 3 OD, 75 MHz) d ppm 14.84, 22.50, 23.99, 54.78, 57.02 109.11, 115.35, 116 , 01, 118.68, 130.72, 131.29, 131.59, 134.26, 159.33 Elemental composition: C, H, N, Cl: theoretical; 70.51, 6.53, 2 , 84, 7.18%, found: 70.31, 6.75, 2.65, 6.89% Example 7 In vivo tests for the bioavailability of androst-5-ene-3β, 17β-diol prodrugs 1) Principle Tests for the bioavailability of the sex prodrugs were carried out on males by measuring the plasma concentrations of the compounds by administration of the compounds. A) Animal eta and therapy Male Sprague-Dawley rats [Crl: CD (SD) Br] weighing 275-350 g were obtained from Charles-River Canada Inc. and housed 2 per cage during the habituation period and individually during the test period. The animal was kept in the winter for 12 hours with an illumination of 12 hours dark (light on at 08:00). The animals were given certified rodent food (Lab Diet # 5002, pellets) and tap water in any amount. Rats were fasted (with water only access) starting the evening before dosing. Each test compound was administered to three animals as a suspension in 0.4% methylcellulose with oral ganglion at a dose of 150 µg / rat. One blood sample of ~ 0.7 ml was collected from the jugular vein of rats under Isoflurane-induced anesthesia at 1, 2, 3, 4, and 7 hours after application of the bulb. The blood samples were immediately transferred to a refrigerated 0.75 ml Microtainer containing EDTA and kept in an ice-water bath until centrifuged at 3,000 rpm for 10 minutes. Plasma separation was performed rapidly (less than 50 minutes) after blood was collected. One aliquot of 0.25 ml of plasma was then transferred to a borosilicate tube (13 x 100) and was quickly frozen on dry ice. The plasma samples were kept at -80 ° C until the plasma concentrations of sex steroids or sex steroid precursors by GC-MS were measured. Results of Oral Absorption and AUC are shown in Figures 12 and 13. Pharmaceutical Composition Examples Below, for example, several pharmaceutical compositions using the preferred EM-800 or EM-1538 active SERM and the preferred DHEA active sex steroid precursor are shown. EM-1304 or EM-01474-D. Other compounds or combinations thereof may be used in place of (or in addition to) EM-800 or EM-1538, DHEA, EM-1304 or EM-01474-D. The concentration of the active ingredient can be varied within a wide range as shown here. The amounts and types of other ingredients that may be combined with c are well known in the art. Example A Tablet Ingredient% by weight (by weight of the whole composition) EM-800 5.0 DHEA 15.0 Gelatins 5.0 Lactose 58.5 Starch 16.5 Example B Gelatin capsule Ingredient% by weight (by weight) total composition) EM-800 5.0 DHEA 15.0 Hydrated lactose 65.0 Starch 4.8 Microcrystalline cellulose 9.8 Magnesium stearate 0.4 Kit Examples Below, some kits using the preferred active SERM EM are illustrated as an example -800 or EM-1538, and the preferred active sex steroid precursor DHEA, EM-1304 or EM-01474-D. Other compounds or combinations thereof may be used in place of (or in addition to) EM-800 or EM-1538, DHEA, EM-1304 or EM-01474-D. The concentration of the active ingredient can be varied within a wide range, as shown here. The amounts and types of other ingredients that may be combined with c are well known in the art. Example A SERM is administered orally and sex steroid precursor is administered transdermally. EN 203 438 B1 27 Composition SERM for oral administration (capsules) Component% by weight (based on the weight of the total composition) EM-800 5.0 Hydrated Lactose 80.0 Starch 4.8 Microcrystalline cellulose 9.8 Magnesium stearate 0.4 Topical sex steroid precursor composition (gel) Ingredient% by weight (based on weight of the total composition) DHEA 10.0 Caprylic-capric triglyceride ( Neobee M-5) 5.0 Hexylene glycol 15.0 Transcutol (diethylene glycol monomethyl ether) 5.0 Benzyl alcohol 2.0 Cyclomethicone (Dow Corning 345) 5.0 Ethanol (absolute) 56.0 Hydroxypropylcellulose ( 1500 cps) (KLUCEL) 2.0 Example B SERM and sex steroid precursor are administered orally. Non-steroidal anti-estrogen composition for oral administration (capsules) Ingredient% by weight (based on the weight of the total composition) EM-800 5.0 Hydrated lactose 80.0 Starch 4.8 Microcrystalline cellulose 9.8 Magnesium stearate 0.4 Steroid precursor composition genital tract for oral administration (gelatine capsule) Ingredient% by weight (based on the weight of the total composition) 1 2 DHEA 15.0 Hydrated lactose 70.0PL 203 438 B1 28 cont. Table 1 2 Starch 4.8 Microcrystalline cellulose 9.8 Magnesium stearate 0.4 Other SERMs can be substituted for EM-800 or EM-01538 in the above compositions as well as other sex steroid inhibitors can be substituted for DHEA , EM-1304 or EM-01474-D. It may link to more than one SERM or more than one precursor, in which case the combined weight percent is preferably the weight percent for the single precursor or the single SERM given in the examples above. PL

Claims (6)

Claims 1. A pharmaceutical composition comprising a dehydroepiandrosterone, a selective estrogen receptor modulator, and a pharmaceutically acceptable excipient, characterized in that it comprises a) a pharmaceutically acceptable excipient, diluent or carrier; b) a therapeutically effective amount of dehydroepiandrosterone, c) a therapeutically effective amount of a triphenylethylene derivative of the general formula wherein D is -OCH 2 CH 2 N (R 3) R 4 or -CH = CH-COOH, R 3 and R 4 independently selected from the group consisting of C 1 -C 4 alkyl or R 3, R 4 and the nitrogen atom to which they are bound together form a ring structure selected from the group consisting of pyrrolidine, dimethyl-1-pyrrolidine , methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino and morpholino; wherein E and K are independently hydrogen or hydroxy; where J is hydrogen or halogen. 2. The pharmaceutical composition according to claim 1 A compound according to claim 1, characterized in that the compound GW-5638 of the following formula is used as a triphenyl ethylene derivative: PL 203 438 B1 A kit characterized in that the first container contains a therapeutically effective amount of dehydroepiandrosterone and comprises a second container containing a therapeutically effective amount of a triphenylethylene derivative as defined in claim 1. 1. 4. Set according to claims A compound according to claim 3, characterized in that it contains the compound GW-5638 of the following formula as the triphenylethylene derivative: 5. The use of dehydroepiandrosterone in the manufacture of a medicament for treating or reducing the risk of acquiring osteoporosis, in combination with a therapeutically effective amount of a triphenylethylene derivative as defined in claim 1. 1 6. Use according to claim 5. A compound according to claim 5, characterized in that the compound GW-5638 of the following formula is used as the triphenylethylene derivative: Figures PL 203 438 B1 31 PL 203 438 B1 32 PL 203 438 B1 33 PL 203 438 B1 34 PL 203 438 B1 35 PL 203 438 B1 36PL 203 438 B1 37PL 203 438 B1 38PL 203 438 B1 39PL 203 438 B1 40PL 203 438 B1 41PL 203 438 B1 42PL 203 438 B1 43PL 203 438 B1 44PL 203 438 B1 45PL 203 438 B1 46 Publishing Department of the Polish Patent Office Price 6, 00 z l. PL