A Pharmaceutical Product for Hormone Replacement Therapy Comprising Tibolone Or a Derivative Thereof and Estradiol Or a Derivative Thereof

Home , Benzestrol, Chlorotrianisene, Diethylstilbestrol, Estradiol valerate, Estriol phosphate, Hypoestrogenism

Europäisches Patentamt *EP001522306A1* (19) European Patent Office

Office européen des brevets (11) EP 1 522 306 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.7: A61K 31/567, A61K 31/565, 13.04.2005 Bulletin 2005/15 A61P 15/12

(21) Application number: 03103726.0

(22) Date of filing: 08.10.2003

(84) Designated Contracting States: • Perez, Francisco AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 08970 Sant Joan Despi (Barcelona) (ES) HU IE IT LI LU MC NL PT RO SE SI SK TR • Banado M., Carlos Designated Extension States: 28033 Madrid (ES) AL LT LV MK (74) Representative: Markvardsen, Peter et al (71) Applicant: Liconsa, Liberacion Controlada de Markvardsen Patents, Sustancias Activas, S.A. Patent Department, 08028 Barcelona (ES) P.O. Box 114, Favrholmvaenget 40 (72) Inventors: 3400 Hilleroed (DK) • Palacios, Santiago 28001 Madrid (ES)

(54) A pharmaceutical product for hormone replacement therapy comprising tibolone or a derivative thereof and estradiol or a derivative thereof

(57) A pharmaceutical product comprising an effec- arate or sequential use in a method for hormone re- tive amount of tibolone or derivative thereof, an effective placement therapy or prevention of hypoestrogenism amount of estradiol or derivative thereof and a pharma- associated clinical symptoms in a human person, in par- ceutically acceptable carrier, wherein the product is pro- ticular wherein the human is a postmenopausal woman. vided as a combined preparation for simultaneous, sep- EP 1 522 306 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 522 306 A1 2

Description [0008] The review article of Journal of Steroid Bio- chemistry and Molecular Biology (2001), 76(1-5), FIELD OF THE INVENTION: 231-238 provides a review of some of these compara- tive studies. It further concludes that tibolone works on [0001] The present invention relates to a pharmaceu- 5 the estradiol receptor. In other words, tibolone and es- tical product comprising an effective amount of tibolone tradiol are both working on the same receptor. or derivative thereof, an effective amount of estradiol or [0009] WO0074684A1 describes numerous different derivative thereof and a pharmaceutically acceptable possible combinations of different steroid hormones for carrier, wherein the product is provided as a combined treatment of postmenopausal women. Virtually all pos- preparation for simultaneous, separate or sequential 10 sible theoretical combinations are listed including differ- use in a method for hormone replacement therapy or ent combinations of estrogens, androgens, progestins, prevention of hypoestrogenism associated clinical selective estrogen receptor modulator (SERM), selec- symptoms in a human person, in particular wherein the tive androgen receptor modulator (SARM) and selective human is a postmenopausal woman. progestin receptor modulator (SPRM). No specific rele- 15 vant actual example results are provided. One list of the BACKGROUND OF THE INVENTION: description is a list of a number of different suitable SERM molecules. This list includes tibolone. Another list [0002] In hormone replacement therapy (HRT), includes a number of different suitable estrogens. This sometimes also referred to as estrogen replacement list includes estradiol. therapy, estrogens are administered to prevent or treat 20 [0010] The article of European Journal of Gynaeco- symptoms resulting from estrogen deficiency or hypoes- logical Oncology, (2002) 23 (2) 127-30 describes a trogenism. Hypoestrogenism can occur in both females study analyzing possible breast cancer risks of tibolone. and males, and can lead to disorders and ailments such The studies are performed in vitro on a human breast as osteoporosis (loss of bone mass), arteriosclerosis, cancer cell line. The aim of the study was to compare climacteric symptoms such as hot flushes (flashes), 25 tibolone to HRT using estradiol and norethisterone. Ti- sweats, urogenital atrophy, mood disturbances, insom- bolone was examined alone and in the presence of 0.1 nia, palpitations. Estrogen deficiency has also been as- nM estradiol. sociated with cognitive disturbances and Alzheimer's disease. SUMMARY OF THE INVENTION: [0003] Hypoestrogenism, and in particular chronic hy- 30 poestrogenism, is frequently observed in perimenopau- [0011] The problem to be solved by the present inven- sal and post-menopausal women. However, it can also tion is to provide a pharmaceutical composition with im- result from hypogonadism or castration, as well as from proved properties in relation to treatment or prevention primary ovarian failure, treatment of e.g. breast cancer of hypoestrogenism associated clinical symptoms, in with aromatase inhibitor and gonadotropin-releasing 35 particular of a postmenopausal woman. Improved prop- hormone analogue treatment of benign gynaecological erties include less unwanted negative side effects such diseases such as endometriosis, adenomyosis, uterine as less risk for breast cancer development. fibroids (leiomyomas), dysmenorrlioea, menorrhagia [0012] As explained above, the prior art describes that and metrorrhagia. tibolone and estradiol are both working on the same re- [0004] Hormone replacement therapy (HRT) has 40 ceptor. Among others, despite of this fact, the present been used for many years for alleviation of hypoestro- inventors investigated the effects of a pharmaceutical genism associated clinical symptoms such as postmen- product combining both tibolone and estradiol. Surpris- opausal symptoms as well as prophylaxis of osteoporo- ingly, they found that such a pharmaceutical product had sis in postmenopausal women. improved properties in relation to treatment or preven- [0005] Suitable estrogens, such as estradiol, have 45 tion of hypoestrogenism associated clinical symptoms, been used in HRT. Estradiol is many times used in com- in particular of a postmenopausal woman. bination with some progestins such as norethindrone (a [0013] Accordingly, a first aspect of the invention re- synthetic progestin also termed norethisterone), me- lates to a pharmaceutical product comprising an effec- droxiprogesterone and others. tive amount of tibolone or derivative thereof, an effective [0006] Tibolone is a synthetic steroid which elicits es- 50 amount of estradiol or derivative thereof and a pharma- trogenic, progestogenic and androgenic properties. Ti- ceutically acceptable carrier, wherein the product is pro- bolone is used as an alternative to estradiol in HRT. vided as a combined preparation for simultaneous, sep- [0007] Numerous studies have been carried out to arate or sequential use in a method for hormone re- compare the effectiveness of tibolone and estradiol on placement therapy or prevention of hypoestrogenism symptoms in postmenopausal women. Generally, all 55 associated clinical symptoms in a human person, in par- these studies are based on that a group of women gets ticular wherein the human is a postmenopausal woman. tibolone and another group gets estradiol or estradiol [0014] A second aspect of the invention relates to use plus a progestin such as norethindrone. of a pharmaceutical product, as described herein, for the

2 3 EP 1 522 306 A1 4 manufacture of a medicament for hormone replacement Derivatives: therapy or prevention of hypoestrogenism associated clinical symptoms in a human person, in particular [0022] This section is a general description of deriva- wherein the human is a postmenopausal woman. tives. Tibolone and estradiol are active components. [0015] This second aspect may alternatively be for- 5 [0023] The active components may be converted into mulated as a method for hormone replacement therapy derivatives thereof, like esters and ethers, which, within or prevention of hypoestrogenism associated clinical a pharmaceutical composition as described herein, are symptoms in a human, in particular wherein the human all covered by the present invention. The derivatives can is a postmenopausal woman, comprising administering be prepared by standard procedures known to one to a human in need thereof an effective amount of phar- 10 skilled in the art. maceutical product as described herein. [0024] Esters and ethers may e.g. be prepared by the [0016] A third aspect of the invention relates to a methods given in the literature, for example, in Ad- method for making a pharmaceutical product for use in vanced Organic Synthesis, 4th Edition, J. March, John a method for hormone replacement therapy or preven- Wiley & Sons., 1992. tion of hypoestrogenism associated clinical symptoms 15 [0025] Generally, a derivative of tibolone denotes in a human person, in particular wherein the human is herein a derivative that at least is capable of triggering a postmenopausal woman, comprising making a phar- a response in vivo that in essence corresponds to the maceutical product comprising an effective amount of response in vivo of tibolone. In order for tibolone to trig- tibolone or derivative thereof, an effective amount of es- ger such a response tibolone normally have to bind to tradiol or derivative thereof and a pharmaceutically ac- 20 tibolone receptors, which receptors are found in various ceptable carrier as described herein. tissues within the human body. A derivative of tibolone denotes herein a derivative that is capable of binding to Embodiment(s) of the present invention is described a tibolone receptor in a similar way as tibolone bind to below, by way of example(s) only the same tibolone receptor. Based on e.g. known 3-di- 25 mensional structure of tibolone and a tibolone receptor DETAILED DESCRIPTION OF THE INVENTION: the skilled person is perfectly capable of making e.g. mi- nor structural modifications of tibolone to get a derivative Tibolone: of tibolone that fulfills the criteria above. [0026] A derivative of estradiol should herein be un- [0017] Tibolone denotes herein the molecule with 30 derstood in the same way, wherein a derivative of estra- Chemical Abstract Service (CAS) name (7α,17α)- diol, of course, has a response in vivo that is corre- 17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn- sponding to estradiol and a receptor binding that is sim- 3-one and CAS registry number 5630-53-5. ilar to the binding estradiol has to the same estradiol [0018] In vivo, tibolone is rapidly converted by the in- receptor. testine and liver into two estrogenic metabolites, 3α-hy- 35 droxytibolone and 3 β-hydroxytibolone, which are re- Pharmaceutical product: sponsible for the drug's estrogenic effects on bone, vaginal tissue and climacteric symptoms. A third metabolite, [0027] The pharmaceutical product may be provided the ∆4-isomer, has progestagenic and androgenic ac- as tivities and is specifically formed in the endometrium. 40 For further details see the review article of Journal of - first container comprising a composition comprising Steroid Biochemistry and Molecular Biology (2001), 76 an effective amount of tibolone or derivative thereof (1-5), 231-238. and a pharmaceutically acceptable carrier; [0019] These tibolone metabolites shall herein be un- - second container comprising a composition com- derstood to be a derivative of tibolone. 45 prising an effective amount of estradiol or derivative thereof and a pharmaceutically acceptable carrier; Estradiol: and - instructions for combined sequential and/or simul- [0020] Estradiol denotes herein the molecule with taneous administration of the compositions of first Chemical Abstract Service (CAS) name (17β)-Estra- 50 and second container for simultaneous or sequen- 1,3,5(10)-triene-3,17-diol; β-estradiol. The CAS registry tial use in a method for hormone replacement ther- number is 50-28-2. apy or prevention of hypoestrogenism associated [0021] Derivatives of estradiol include closely related clinical symptoms in a human person. molecules such as estradiol valerate, estradiol benzoate, α-estradiol or estradiol 17β-Cypionate. 55 [0028] The term "container" should be understood broadly as some kind of physical item. It could e.g. be a tablet, an injector, a capsule etc. [0029] Alternatively, the pharmaceutical product may

3 5 EP 1 522 306 A1 6 be a pharmaceutical composition comprising both tibo- tablets, capsules, granules, powders, emulsions, sus- lone and estradiol. Accordingly, an embodiment of the pensions, or solutions. invention relates to a pharmaceutical composition com- [0037] Without being limited to theory, it is believed prising an effective amount of tibolone or derivative that tibolone, among others, provides the effect of a pro- thereof, an effective amount of estradiol or derivative 5 gestin. Accordingly, in the pharmaceutical product it is thereof and a pharmaceutically acceptable carrier for not considered necessary to include progestins such as use in a method for hormone replacement therapy or norethindrone (a synthetic progestin, also termed nore- prevention of hypoestrogenism associated clinical thisterone) or medroxiprogesterone. Accordingly, a pre- symptoms in a human person. ferred embodiment of the invention relates to a pharma- [0030] Preferably, the composition comprises from 1 10 ceutical product, as described herein, that does not µg to 10 mg of tibolone or derivative thereof, more pref- comprise norethindrone or medroxiprogesterone. erably from 50 µg to 5mg of tibolone or derivative there- [0038] Examples of auxiliaries and/or excipients of. which may be mentioned are tragacanth, lactose, talc, [0031] Preferably, the composition comprises from 1 agar, polyglycols, ethanol, and water. It is also possible µg to 10 mg of estradiol or derivative thereof, more pref- 15 to administer the active substances as such, without ve- erably from 50 µg to 5mg of estradiol or derivative there- hicles or diluents, in a suitable form, for example, in cap- of. sules. [0032] By "pharmaceutically acceptable carrier" as [0039] Preferably, the pharmaceutical product, as de- used herein is meant one or more compatible solid or scribed herein, is provided together with suitable phar- liquid filler diluents, or encapsulating substances. By 20 maceutically relevant instructions. The instructions pref- "compatible" as used herein is meant that the compo- erably explain pharmaceutically relevant information nents of the composition are capable of being commin- such as e.g. qualitative and quantitative of composition, gled without interacting in a manner which would sub- pharmaceutical form, therapeutic indications and meth- stantially decrease the pharmaceutical efficacy of the to- od of administration (including recommend doses). tal composition under ordinary use situations. 25 [0033] Some examples of substances which can Use for the treatment of clinical symptoms: serve as pharmaceutical carriers are sugars, such as lactose, glucose and sucrose; starches such as corn [0040] The HRT method according to the invention starch and potato starch; cellulose and its derivatives may advantageously be used to treat all known forms such as sodium carboxymethycellulose, ethylcellulose 30 of hypoestrogenism, e. g. hypoestrogenism associated and cellulose acetates; powdered tragancanth; malt; with peri-menopausal and post-menopausal women, gelatin; talc; stearic acids; magnesium stearate; calcium hypoestrogenism resulting from hypogonadism or cas- sulfate; vegetable oils, such as peanut oils, cotton seed tration, as well as hypoestrogenism resulting from pri- oil, sesame oil, olive oil, corn oil and oil of theobroma; mary ovarian failure, treatment of e. g. breast cancer polyols such as propylene glycol, glycerine, sorbitol, 35 with aromatase inhibitor and gonadotropin-releasing manitol, and polyethylene glycol; agar; alginic acids; wa- hormone analogue treatment of e. g. benign gynaeco- ter; pyrogen-free water; isotonic saline; and phosphate logical diseases. Examples of manifestations of hypoes- buffer solution; skim milk powder; as well as other non- trogenism that can effectively be treated or prevented toxic compatible substances used in pharmaceutical with the present method in both females and males in- formulations. 40 clude osteoporosis, arteriosclerosis, cognitive distur- [0034] Wetting agents, fillers and lubricants such as bances and Alzheimer's disease. The method may also sodium lauryl sulfate, as well as coloring agents, flavor- advantageously be used in the (prophylactic) treatment ing agents, lubricants, excipients, tabletting agents, sta- of climacteric symptoms such as hot flushes (flashes), bilizers, anti-oxidants and preservatives, can also be sweats, urogenital atrophy, mood disturbances, insom- present. 45 nia and palpitations. The present method is particularly [0035] A pharmaceutical product as described herein suited for treating or preventing osteoporosis and cli- can be administered orally, intramuscularly, intrave- macteric symptoms. nously, transdermally, subcutaneously or by other [0041] Virtually all postmenopausal and perimeno- modes of administration. Preferably, the pharmaceutical pausal women can be treated with the methods of the product can be administered orally. 50 invention. If desired, such a woman can be identified as [0036] A pharmaceutical product, as described here- being in need of hormone replacement therapy (using in, may include other pharmaceutically active substanc- standard criteria, as described, for example, by the es. It can be prepared by mixing the active compounds American College of Physicians Guidelines (incorporat- with one or more pharmacologically tolerated auxiliaries ed herein by reference)) prior to treatment of the woman and/or excipients such as, for example, fillers, emulsifi- 55 with the pharmaceutical product as described herein. A ers, lubricants, masking flavors, colorants, or buffer sub- variety of therapeutic regimens are suitable for use in stances, and converting the mixture into a suitable phar- the invention, and practitioners of ordinary skill in the art maceutical form such as, for example, tablets, coated can readily optimize a particular regimen for a particular

4 7 EP 1 522 306 A1 8 woman by monitoring the woman for signs and symp- hormone replacement therapy or prevention of hypoes- toms of hormone deficiency, and increasing or decreas- trogenism associated clinical symptoms in a human per- ing the dosage and/or frequency of treatment as de- son. sired. [0051] All other aspects and embodiments described [0042] Preferably, the human to be treated is a post- 5 herein with respect to a pharmaceutical product and its menopausal woman. related uses and method for making it are also aspects [0043] The term a "postmenopausal" woman is one and preferred embodiments with respect to this sepa- who in the absence of hormone replacement therapy or rate aspect of the invention. other medication would experience at least 12 months [0052] An "estrogen" is an agent, natural or synthetic, of amenorrhea or levels of serum follicle-stimulating hor- 10 that exerts biological effects characteristic of estrogenic mone greater than 30 mIU/ml. Menopause is the period hormones such as estradiol. As used herein, the term of natural cessation of menstruation occurring usually "estrogen" also encompasses "conjugated estrogens," between the ages of 45 and 50. Accordingly, a postmen- which are an amorphous preparation of naturally occur- opausal woman may alternatively be defined as a wom- ring, water soluble, conjugated forms of mixed estro- an that has had the menopause. 15 gens that typically are obtained from the urine of preg- [0044] A "perimenopausal"woman is one who in the nant mares (e.g., sodium estrone sulfate). absence of hormone replacement therapy or other med- [0053] Examples of suitable estrogens include, with- ication would experience a change in her intermenstrual out limitation, estradiol valerate, estradiol benzoate, es- cycle interval and have associated symptoms of estro- tradiol, estradiol cypionate, estrone, piperazine estrone gen deficiency, such as vasomotor flushes, vaginal dry- 20 sulfate, estriol, estriol hemisuccinate, ethinylestradiol, ness, and worsening premenstrual syndrome. Also in- polyestradiol phosphate, estrone potassium sulfate, cluded are women who in the absence of hormone re- benzestrol, chlorotrianisene, methallenestril, dienestrol, placement therapy or other medication would experi- diethylstilbestrol diphosphate, mestranol, diethyles- ence less than 12 months of amenorrhea. tilbestrol (DES), quinestranol, phytoestrogens, animal- [0045] Regardless of the route of administration, the 25 derived estrogens (e.g., equine estrogens), and meta- estrogen typically is administered at a dosage of 1 µg/ bolic derivatives of animal-derived estrogens. kg to 10 mg/kg (e.g., 5 µg/kg to 5mg/kg). The tibolone is typically is administered at a dosage of 1 µg/kg to 10 EXAMPLES: mg/kg (e.g., 5 µg/kg to 5mg/kg). [0046] The pharmaceutical product can be adminis- 30 Example 1: Combined estrogen/tibolone treatment tered in multiple doses per day, if desired, to achieve the total desired daily dose. Typically, the human will be Introduction: treated over the course of several months or years, or even life-long to ameliorate the signs and symptoms. [0054] The principal objective of this study was to in- [0047] In a typical therapeutic regimen, the pharma- 35 vestigate the possibility of utilizing tibolone as a proges- ceutical product is administered to the human at least tin in a combined estrogen/tibolone treatment of meno- once daily (e.g., orally, subcutaneously, or delivered by pausal problems. transdermal or depot methods) for at least days, at the dosages listed above. Preferably the pharmaceutical Material and methods product is administered orally to the human. 40 [0048] Examples of clinical symptoms of a post men- [0055] 112 Wistar female rats were used. 96 were opausal woman are osteoporosis, increased cholesterol castrated at 3 month age. The rats were split into follow- levels that leads to atherosclerosis, depression, head- ing experimental groups (n=16): The rats of groups A to aches, nausea or climacteric symptoms. F were castrated. Group G was not castrated. All doses 45 were given via subcutaneous (SC) route. A separate aspect of the invention: Group A: received estradiol valerate (E2) at a dose [0049] Without being limited to theory, it is believed of 50 µg/Kg/week; that the present invention works in a beneficial manner Group B: received tibolone at a dose of 1 mg/Kg/ not only with estradiol and its derivatives but with estro- 50 day; gens in general. Group C: received a combination of E2 and tibolone [0050] Accordingly a separate aspect of the invention at the same doses as given for group A and B; relates to a pharmaceutical product comprising an ef- Group D: was as group C but only with a tibolone fective amount of tibolone or derivative thereof, an ef- dose of 0.5 mg/Kg/day; fective amount of an estrogen or derivative thereof and 55 Group E: received E2 together with noretisterone at a pharmaceutically acceptable carrier, wherein the a dose of 0.5 mg/Kg/day; product is provided as a combined preparation for si- Group F: was a control group of castrated rats; multaneous, separate or sequential use in a method for Group G: was a control group of not castrated rats

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[0056] The drugs were dissolved in oil before inocu- uct is provided as a combined preparation for simul- lation. The days the groups got combined treatment of taneous, separate or sequential use in a method for 2 drugs this was done separately at two different inoc- hormone replacement therapy or prevention of hy- ulation points. All treatments were started one week af- poestrogenism associated clinical symptoms in a ter castration. 5 human person. [0057] After 15 days of treatment 8 rats in each group were sacrificed. In all animals were determined: 2. The pharmaceutical product of claim 1, wherein the pharmaceutical product is provided as: • weight and size of uterus • blood plasma levels of LH 10 - first container comprising a composition com- • hypophysis levels of LH prising an effective amount of tibolone or derivative thereof and a pharmaceutically accepta- [0058] After 30 days the rest of the rats were sacri- ble carrier; ficed and the same data was determined. The data was - second container comprising a composition determined using standard methods. All data were sta- 15 comprising an effective amount of estradiol or tistically analyzed by standard methods. derivative thereof and a pharmaceutically acceptable carrier; and Results: - instructions for combined sequential and/or simultaneous administration of the compositions [0059] The relative weight of uterus (g uterus/Kg rat 20 of first and second container for simultaneous weight) alter 15 days were approximately equal in all or sequential use in a method for hormone re- groups except the castrated control, which had a signif- placement therapy or prevention of hypoestro- icantly lower uterus weight. At 30 days the results were genism associated clinical symptoms in a hu- similar. The castrated control group still had the lowest man person. weight. However, here the group only getting tibolone 25 had a uterus weight that was some grams lower than 3. The pharmaceutical product of claim 1, wherein the the rest. pharmaceutical product is a pharmaceutical com- [0060] With respect to the plasma LH levels, the tibo- position comprising an effective amount of tibolone lone only and castrated control group had the highest or derivative thereof, an effective amount of estra- levels. This was both at 15 and 30 days. However, at 30 30 diol or derivative thereof and a pharmaceutically ac- days the tibolone only group had LH levels below the ceptable carrier for hormone replacement therapy castrated control group. or prevention of hypoestrogenism associated clini- [0061] With respect to hypophysis levels of LH, after cal symptoms in a human person. 30 days treatment the highest levels were observed in the tibolone only and castrated control group. 35 4. The pharmaceutical product of any of claims 1 to 3, wherein the pharmaceutical product comprises a Discussion: composition comprising from 50 µg to 5mg of tibolone or derivative thereof and a composition com- [0062] From the uterus weight data one may deduce prising from 50 µg to 5mg of estradiol or derivative that the combination estrogen/tibolone has an estrogen 40 thereof. / progestin effect similar to the known estrogen/noretisterone standard. 5. The pharmaceutical product of any of claims 1 to 4, [0063] The plasmatic LH data demonstrates the fun- wherein the pharmaceutical product comprises ti- damental estrogen action on feed back regulation of hy- bolone and β-estradiol. pophysis secretion. All estrogen groups had levels cor- 45 responding to the not castrated control group. 6. The pharmaceutical product of any of claims 1 to 5, [0064] The hypophysis data demonstrates the pro- wherein the human is a postmenopausal woman. gestin effect of the tibolone/estrogen combination. At 30 days the hypophysis LH levels of the tibolone/estrogen 7. Use of a pharmaceutical product, of any of the pre- groups were similar to the not castrated control group. 50 ceding claims, for the manufacture of a medicament for hormone replacement therapy or prevention of hypoestrogenism associated clinical symptoms in a Claims human person.

1. A pharmaceutical product comprising an effective 55 8. The use of claim 7, wherein the human is a post- amount of tibolone or derivative thereof, an effective menopausal woman. amount of estradiol or derivative thereof and a pharmaceutically acceptable carrier, wherein the prod- 9. The use of any of claims 7 to 8, wherein the tibolone

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or derivative thereof is administered at a dosage from 5 µg/kg to 5mg/kg and the estradiol or derivative thereof is administered at a dosage from 5 µg/ kg to 5mg/kg. 5 10. The use of any of claims 8 to 9, wherein the clinical symptoms of a postmenopausal woman are osteoporosis, increased cholesterol levels that lead to atherosclerosis, depression, headaches, nausea or climacteric symptoms, and wherein the pharmaceu- 10 tical product is administered orally to the woman.

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