SA112340084B1 - Androgenic pharmaceutical compounds with low estrogenic effect - Google Patents

Abstract

Novel methods for treating or reducing the likelihood of acquiring symptoms or diseases due to the menopause, in postmenopausal women, particularly osteoporosis, vaginal atrophy and dryness, hypogonadism, diminished libido, skin atrophy, connective tissue disease, urinary incontinence, breast, endometrial, ovarian and uterine cancers, hot flashes, loss of muscle mass, insulin resistance, fatigue, loss of energy, aging, physical symptoms of menopause, in susceptible warm-blooded animals including humans involving administration of a sex steroid precursor are disclosed. Said method comprising novel ways of administering and dosing dehydroepiandrosterone (DHEA) in order to take advantage of positive androgenic effects in the vaginal layers lamina propia and/or the layer muscularis, without undesirably causing systemic estrogenic effects in order to avoid the risk of breast and uterine cancer. Pharmaceutical compositions for delivery of active ingredient(s) useful to the invention are als

Description

— \ — Androgenic pharmaceutical compounds with low estrogenic effect Full Description Background This application is a partial application of Application No. 8794984 which was filed in the Kingdom of Saudi Arabia on AY EY [ASA] corresponding to 01 + to Yr A The present invention provides novel methods of administration and dosing of dehydroepiandrosterone (DHEA) to take advantage of its positive androgenic effects (eg in vaginal layers, lamina propia and/or muscle layers). layer muscularis without producing undesirable group estrogenic effects. In addition to DHEA, other sex steroids can be used (such as: dehydroepiandrosterone - 181n9-0 sulfate and androst-e-ene- BY 178-diol a0nc38,178-0 androst-5-ene—"or ;-androstene-"-11-androstene—3,17-dione—£. Many hormone-related therapies, for example, many supply the sex steroids jie estrogen or systemic and/or target tissue. In addition to the direct administration of androgens and/or estrogens, sex steroid precursors that can be converted to estrogen and/or 00 in a tissue are used in many cases. Both androgens may be Sade estrogen in some cases and harmful in Al cases depending among other things; on the target tissue; the specific needs of the patient and the extent to which non-target tissue may be affected. Some treatments may be; Although targeting unwanted activity elsewhere in the body (eg, topical administration of a pharmaceutical agent still increases the presence of oeYoAY)

- so

The pharmaceutical preparation or one of its metabolites in the body systems. Also did not understand

The mechanism of action is understood, especially the relative contributions of estrogen and hormones.

General description of the invention

The present invention aims to use doses; Specific formulations and administration methods are used to achieve the beneficial effects

© SEX Steroids better and avoid their unwanted side effects.

on one side; The invention provides a method for treating and/or reducing the possibility of vaginal diseases

Vaginal diseases or conditions associated with hormonal imbalance in

Postmenopausal women, where the method includes

Mentioned on administering a sex steroid precursor selected from the 0 group comprising:

dehydroepiandrosterone, dehydroepiandrosterone —sulfate, androst-5-

ene-3.beta.,17.beta.—diol, and 4-androsten—3,17—-dione

to a patient in need of such treatment; Where sale aad is a producer of sex steroids

androgen in a therapeutic amount that increases the level of normal androgen steroid precursor metabolism that shall not exceed the values found in Jef estradiol without increasing the level of metabolites Vo

In the aspect of AT the invention provides a method for treating and/or reducing the possibility of developing symptoms or diseases

Resulting from menopause (cmenopause) in postmenopausal women;

Where the aforementioned method includes administering a substance that produces sexual steroids selected from group 0, which includes:

dehydroepiandrosterone, dehydroepiandrosterone —sulfate, androst-5-

ene-3.beta.,17.beta.—diol, and 4-androsten—3,17—-dione

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— ¢ — to a patient in need of such treatment; Where a sale sex steroid precursor is given in a therapeutic amount that increases the level of turnover of androgen metabolites without increasing the level of turnover of estradiol higher than the values found in a normal shall that no longer menstruates To avoid the risk of breast and uterine cancer ©.cancer. In another aspect, the invention provides Riya for the treatment and/or reduction of the possibility of developing symptoms or diseases resulting from menopause; In postmenopausal women, where the aforementioned method includes giving a substance that produces sexual steroids selected from the group that includes: dehydroepiandrosterone, dehydroepiandrosterone —sulfate, androst-5- ene-3.beta.,17.beta.- diol, and 4-androsten-3,17-dione \. to a patient in need of such treatment; A sex steroid-producing sale is given in a therapeutic amount that increases the turnover of androgen metabolites and also includes administration as part of a combination therapy; A therapeutically effective amount of selective estrogen receptor modulator to avoid the risk of developing uterine and uterine cancer, a tale that afflicts women in postmenopausal age, and to prevent bone loss, fat accumulation, fat 70, and diabetes 01866185 The second kind. In the aspect of AT, the invention provides a method for the treatment of vaginal conditions affecting the lamellae propria or the layer muscularis, including administration of DHEA transvaginally in a daily dose ranging from ? to 11 mg. 0 In the AT side the invention provides a pharmaceutical composition comprising a sex steroid producing sale selected from the group comprising: dehydroepiandrosterone, dehydroepiandrosterone —sulfate, androst-5-ene-3.beta.,17.beta. —diol, and 4-androsten—3,17—-dione oY AY

It also includes an excipient or a pharmaceutically acceptable diluent or dlls selected from the group containing triglycerides of 012-18 saturated fatty acids having varying amounts of partial 05 glycerides Analogues (solid fats; Bailly (Witepsol) and triglycerides © blended with: oleic; palmitic; and citrate acid 516806. (Kakar butter); hydrogenated cottonseed oil Partially hydrogenated fatty alcohols (Cotomar) lls and 5 esters (<Dehydag Base |, Base 11, or Base lll) may also contain glycerides of saturated fatty acids It contains fatty acids (C12-16) and triglycerides derived from palm, palm kernel, and coconut oils containing glyceryl monostearate 5 polyoxyl citrate (Fattibase) stearate, 95 Base 18106" and higher grade fir fractions from coconut and palm kernel oil “(Hydrokote) palm kernel oil, hydrogenated and reformatted vegetable oils (-5) ((S-070-XXA 5 70-5) and Jew’s Fusion Blend of Primary Glycerides; 0, DIP and TRIPLE derived from natural vegetable oils ((SUPPOGIFE) and triglycerides compounds and Tween YY triglycerides derived from coconut oil (Wecobee) and theobroma oil and glycerides “(Japocire, Ovucire) semi-synthetic and mixture of primary, di- and tri-glycerides derived from saturated fatty acids (Massa Estarinum) and combinations thereof (see 2008 (Allen et al. This invention provides carriers that include liquids in which DHEA and other precursors are ALE for solubility.In another aspect, the invention provides a vaginal suppository comprising citrate-3, cid more specifically +0,0 percent of DHEA by weight Les to total weight of the suppository; of DHEA and also includes a lipophilic excipient A particularly suitable excipient Yo excipient is H-15 50M11/116.oY AY

- a -

By providing the required androgenic effects without systemic estrogenic effects

estrogenic systemic; Systemic estrogenic side effects can be avoided; Jie increased risk

Breast cancers and endometrial endometrium

Which are found in local systemic replacement therapies that

systemic estrogen and systemic estrogen clade based on ©

Labrie, Cusan et al.

Menopause, in press) replacement

In addition to other images for giving cadministering productive materials, the invention provides vaginal suppositories

vaginal suppositories and vaginal creams are formulated using excipients

Preferred excipients and preferred concentrations of the substance 0 produced.

Vaginal administration is preferred because local action produces desired androgen effects

On the vaginal layers required in doses J much more than if administered through

post path. Doses can also be determined by other means of administration by changing previous doses and concentrations

To make a known difference between routes of administration. The resident physician may vary doses as appropriate according to the individual patient's response.

in preferred models; The substance that produces sex steroids is DHEA

Brief description of the graphics

Figure (1): Shows serum levels 5611170 for DHEA and 5-Diol on day 1 or day 17

In a number of women aged 0 75-4 who had a missed period after daily administration of 70 -70 for vaginal suppositories containing 670 70.5 21.0 or 71.8 DHEA expressed data

with the mean SEM + (number - 9 or .01).

Figure 7: Levels in serum Testo Iserum and 0111 on Day 1 or Day 1 of

A number of women aged 40-75 who have had their period stopped after daily administration

And

Ed for vaginal suppositories containing 0 7 70,5 21.0 or 71,8 of 015/8 (N = 4). Data are expressed as mean + SEM (n = A to 9). Testo levels from one patient in the placebo group were excluded due to idiopathic 16510 levels not seen in any other steroid. © Figure 7: Serum 560007 levels for 1 and 2 on Day 1 or Day 1 in women 75-46 years of age who have had a missed period after daily administration of vaginal suppositories containing 70 70 5, 21.0 or 71.8 of DHEA expresses the data as median SEM + (n = 9 or fie 01) and 01. Figure (;): shows levels in serum 5600000 L S-DHEA; S-E1 on day 1 or (asd) 0 *a in a number of OU women aged 00?-75 who had a missed period after daily administration of vaginal suppositories containing dive 7 0 721.0 or ZV, A of DHEA Data are expressed as the mean SEM + (number - 9 or 01). Figure (*): Shows levels in serum ADT-G4-Dione Iserum in Day 1 or Day 1 in a number of women 40-75 years of age who had missed their period after daily administration of Vo vaginal suppositories containing dip 7 0 21.0 or ZV A from DHEA Data are expressed in mean SEM + (number - 9 or 01). Figure (1): shows the levels in serum of 3.alpha.- 3.alpha.-Diol-3G 0101- 6 on day 1 or day 1 in a number of women aged 5-41 who had a missed period 1 day after administration of vaginal suppositories containing 760 76.5 Yo 21.0 or 21, 8 of (DHEA) data are expressed as mean SEM + (number - 9 or 01). Jal (7): shows average serum concentration over twenty-four hours (1 4/8 060 hours) L DHEA-S, 4-Dione (DHEA ,5-010 18510 & 0111 Measurement Per Day 1 or day 1 1 day after administration of a vaginal suppository containing 770 de 21.0 or AVA of DHEA. Data are expressed as mean SEM + (number = A to .)01 Excluded Testo OV AY levels

—A—

From an aly patient in the placebo group (A = all) placebo group in that group). Serum steroid concentrations measured in a number of women aged 0-71 who were not off cycle were added as a reference. Data are expressed as mean (EY =) while the 5th and 95th estimators are indicated (dashed lines). 0 * m less than 0.05 ** m less than (asl) Lad coo) 7) vs. satisfactory treatment

(1 asl) placebo (for YE/AUCO). Shows the average serum concentration over twenty-four hours (Jal 4) and 1-5 measured in E2 (El (3.alpha.-Diol-3G). ,3.alpha.-Diol-17G 01-6 after daily administration of vaginal suppositories containing 70 70,5 21.0 or 1 or day 1 day

21.80 of DHEA. Data are expressed as mean + SEM (n = 9 or 0). Serum steroid concentrations measured in a number of women aged 70-72 who had not interrupted their cycle were added as reference. Data are expressed as mean (EY = nN) while the 5th and 95th doses are indicated (dashed lines).* pe less than 0.05 **; m less than 0.00 trial (day (V) vs placebo placebo (day 1).

Figure 1: Changes in serum levels of ADT-G androgen metabolites ©10101-17-.3.8108 in postmenopausal women with vaginal atrophy vaginal atrophy after intravaginal administration of excessive doses of DHEA The data are expressed as a ratio of serum levels of the same steroid metabolites observed in

Yo premenopausal young women (ages 72-71). The conversion level is obtained by dividing the total serum levels of 3.alpha.-diol-17G ; 3.alpha.-diol-3G (ADT-G) in women receiving DHEA doses of 70.5 720.0 and 71.8 over values found in premenopausal women (data from 2006 (Labrie et al., serum DHEA level changes compared to normal pre-menopausal women)

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— q —

Cycle interruption in comparison to indicate conversion efficiency: (0--<<-1) and-levels

Basic androgen metabolites (DHEA 5 androgen metabolites, respectively.

Figure (01): showing the maturation index 0 and the vaginal pH

pH (b) measured on day 1 and day 1 in a number of women aged 15-400 who had

© Menstruation stopped after daily administration of vaginal suppositories containing 70 76.5 71.6

That is 71.48% of DHEA

Data are expressed as mean SEM + (N = q or p”¢* 0 Yo less than before **¢ P less than

Character data on day 7 vs data on day 1

(Fig. 11) androst- 0 dehydroepiandrosterone (DHEA): indicates 3538 residue time after administration of a serum dose in serum 5-ene-3.beta.,17.beta.—diol (5- diol) (B) 0

Oral single consisting of two DHEA capsules of 500 mg each or placenta; grams of cream

Or Gel 701 DHEA for postmenopausal women.

Figure (VY) shows 5538 time-to-live:

androstenedione (4-dione) (A) and testosterone (B) in serum after VO single oral administration of two DHEA capsules of 50 mg each or placement of §

701 g cream or gel for postmenopausal women.

estrone (E.sub.1) (A) and 17.beta.-estradiol (Fig. 1): $58 shows a survival time

(E.sub.2) (B) in serum after a single oral dose of two capsules

DHEA 58 mg each or apply 4 gm of 7201 DHEA cream or gel for Ye postmenopausal women.

dehydroepiandrosterone sulfate (DHEA-S) (A) Figure $538 shows a survival time (£1:1)

and estrone sulfate (E.sub.1-S) (B) in serum after single dose administration via

Bad

-1 “= oral consisting of two DHEA capsules of 100 mg each or placenta; 201 g cream or gel for postmenopausal women. Figure (15): shows 3538 survival times for androsterone glucuronide (ADT-G) (A) and androstone 3.alpha.,17.beta.—diol-glucuronide (3.alpha.-diol-G) ( B) in © Serum 560100 after daily oral administration of two 50 mg capsules of DHEA or application of 201 g DHEA cream or gel to postmenopausal women. 16) $538 shows the survival time of dehydroepiandrosterone (DHEA) 0 and andros— 3-806-3.0618.,17.5618.-0101 (5-diol) (B) in serum after administration of a dose of 0 daily by mouth for two capsules of 50 mg each of DHEA or application of 4 gm of cream or gel 701 DHEA for postmenopausal women. Measurements were taken on the fourth day KE (71):_shows 8 survival times for androstenedione (4-dione) (A) and testosterone (B) in serum after daily oral administration of two V0 capsules of 500 mg L DHEA each or placement gm of aif or 701 DHEA gel for postmenopausal women Measurements were made on the 14th day of dosing Figure (18): 358 survival times (E2) estradiol 0 (El) estrone in serum after daily oral administration of two capsules of 50 mg each for DHEA or placement? 701g of DHEA cream or gel for postmenopausal women. Measurements 0 were made on the 14th day of dosing. Figure (19): $58 shows the survival time of dehydroepiandrosterone sulfate (DHEA-S) (A) and estrone sulfate (E.sub.1-S) (B) in serum after administration of a daily dose of Oral route of two capsules of 500 mg each of DHEA or application of 2 g cream or gel.

-1 \ —_ 701 DHEA for postmenopausal women. Measurements were made on the 14th day. Figure (0g): Et shows the survival time of: androsterone glucuronide (ADT-G) (A) and androstene- 3.alpha.,17.beta.~diol-G ( 3.alpha.-diol-G) (B)© after daily oral administration of two capsules of 50 mg of DHEA or placenta? 701g of DHEA cream or gel for postmenopausal women. Measurements were taken on the fourteenth day of dosing. Figure (71): shows the ratios of the values of 8060 for a period of 4 7 hours DHEA and its metabolites 0 metabolites on the fourteenth day of dosing compared to the baseline values before treatment. The corresponding numerical values can be identified in Table 5. Jal (77): shows the effect of doses of (Prasterone) DHEA administered daily at 70.6 2.9 and 20.1 intravaginally for a period of A cf oF and 11 weeks on the basis of the sal ratio of adjacent vaginal cells of vaginal parabasal cells in women of age after Vo cycle interruption Data are expressed as mean + SEM Figure (73): shows the effect of (Prasterone) DHEA doses given daily by 70.6 5 2, 9 and 20.1 intravaginally for A cf oF and 11 weeks based on the sal percentage of superficial vaginal cells in postmenopausal women Data are expressed as mean + SEM. (74): The effect of (Prasterone) DHEA doses administered Ley 70.6 5 7.59 and 20, intravaginally cf oF sad 8 and 11 weeks based on vaginal pH 011 in Vaginal Women of postmenopausal age n Data are mean + SEM.

yy

Jovy, which is given daily in the ratio of (Prasterone) DHEA Figure (75): shows the effect of doses per week based on the change in the intensity of 11, 4 cf 2.9 and 21, inside the vagina for a period of 5-7 felt by the women themselves As the order vaginal atrophy symptoms of vaginal atrophy . + SEM with an average of af and expresses 1 as the most disturbing. Comparing values per day Figure (76): shows the effect of doses of (Prasterone) DHEA given daily by 70.6 Jala 20.1 and ee 8 vaginal A cf oF sad and 1 week based on the change in vaginal secretions dada ) Vaginal secretions at vaginal examination .examination Data are expressed as mean + SEM. Figure (77): Shows the effect of doses of (Prasterone) DHEA given daily by 20.6 Yo 0 20.5 and 21.1 intravaginally for a period of cf oY 8 and 11 weeks based on the change in the color of the vagina upon vaginal examination . Data are expressed as mean + SEM. Figure (78): The effect of doses of (Prasterone) DHEA given daily by Jovy 8 2.5 and 70.1 intravaginally of oF sad 4 and 11 weeks on the basis of change in the consistency of the vaginal epithelium epithelial integrity on vaginal examination. The data is expressed as an average of + SEM 10 20.6 given daily by (Prasterone) DHEA. Figure (75): shows the effect of doses

Aa weeks based on change in 11, 8 cf oF sad intravaginally 70.1 and 2.5 8 evaluator on vaginal examination. Data expresses vaginal epithelial thickness + SEM. Serum averaged — (AUG) over twenty-four hours. It shows average concentrations in serum:1 (Fig. 10 2p and 21-5 Measured on 2 days (El «S-DHEA (5-Diol (DHEA) l (Y¢/icl. 4 containing vaginal ovule administration) 1 day after vaginal ovule administration Vy concentrations were added.) 01 = + (number SEM over 5, 7/p1a0a). Data are expressed as the average measured for a number of women who did not have a missed period and reported serum steroid OV AY

— \ _ Their ages 25-71 (n = (£Y) and also for a number of women who have stopped menstruating and their ages are 10-00 (n = 79) as reference data expressed as the mean of the two ratios * and 0 (dashed lines) ,* 0 less than 000 (#*#* 0 less than 0) co experiment vs baseline. (Data from 2008 (Labrie, Cusan et al.) © Figure (1©):_shows mean concentrations in the serum within twenty-four hours

4-Dione, testosterone, DHT ADT-G, 3.alpha.—diol-3G (hr) for Y ¢ JAUCO) oval sale and 7 after 1 day of administration 1 measured in 2 days 800 3.alpha .-diol-17G contains 0 01/7. Data are expressed as vaginal ovule administration (vaginal ovule administration). Measured serum steroid concentrations were added at a number of 01 = + (the number SEM with an average).

0 Women whose periods have not stopped and their ages are .: 0-7? (n = 7;) and for a number of women who had stopped menstruating and their ages are 15-255 (n = 969) as reference data, lie was expressed with the mean of the two homeostasis ratios 50 40 (dashed lines).* + 8 less than 65 experiment vs. value the basic. (Data from 2008 (Labrie, Cusan et al.). Description 1 for more detail:

Vo Below is a list of the articles in this document quoting in short: Archer, D.

F. (2007). 'Drospirenone-containing hormone therapy for postmenopausal women.'

Perspective on current data." J Reprod Med Suppl): 159-64. 52(2 Ayton, R.

A., G.

M.

Darling, et al. (1996). A comparative study of safety

and efficacy of continuous low dose oestradiol released from a vaginal 0 ring compared with conjugated equine oestrogen vaginal cream in the treatment of postmenopausal urogenital atrophy.” Br J Obstet Gynaecol 103(4): 351-8.

oy AY

_\¢ —_

Bachmann, G., R.A. Lobo, et al. (2008). “Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial.” Obstet Gynecol 111(1): 67-76.

Bachmann, G. A., M. Notelovitz, et al. (1992). "Long~term non-hormonal treatment of vagina dryness." J Clin Practical Sex §. o

Baker, V. A and A 8. Jaffe (1996). Clinical uses of 80165009605.

Obstet Gynecol Surv 51:45-59.

E.E. Baulieu, G. Thomas, S. Legrain, N. Lahlou, M. Roger, B. Debuire,

V. Faucounau, L. Girard, M.P. Hervy, F. Latour, M.C. Leaud, A.

Mokrane, H. Pitti-Ferrandi, C. Trivalle, O. de Lacharriere, S. Nouveau, B. \.

Rakoto—Arison, J.C. Souberbielle, J. Raison, Y. Le Bouc, A. Raynaud, X.

Girerd and F. Forette, Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue,

Proc. Natl. Acad. Sci. U.S.A. 97 (2000), MM 4279-4284.

Baxendale, P.M., M.J. Reed, et al. (1981). “Inability of human 10 endometrium or myometrium to aromatize androstenedione.” J Steroid

Biochem 14(3): 305-6.

Belanger, B. Candas, A. Dupont, A. Cusan, P. Diamond, J.L. Gomez and

F. Labrie, Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men, J. Clin. Endocrinol. 0

Metab. 79 (1994), p. 1086-1090.

Belanger, G. Pelletier, F. Labrie, O. Barbier and S. Chouinard,

Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans, Trends Endocrinol. oy AY

_ \ Aj Metab. 14 (2003), p. 473-479.

Beral, V. (2003). Breast cancer and hormone-replacement therapy in the

Million Women Study.” Lancet 362(9382): 419-27.

Beral, V., D. Bull, et al. (2005). “Endometrial Cancer and Hormone Replacement Therapy in the Million Women Study.” Lancet 365(9470): © 1543-51.

Berger, L., M. EI-Alfy, et al. (2005). effects of dehydroepiandrosterone,

Premarin and Acolbifene on histomorphology and sex steroid receptors in the rat vagina.” J Steroid Biochem Mol Biol 96(2): 201-15.

Bulun, S.E., Z. Lin, et al. (2005). “Regulation of aromatase expression in “estrogen-responsive breast and uterine disease: from bench to treatment.” Pharmacol Rev 57(3): 359-83.

J.E. Buster, P.R. Casson, A.B. Straughn, D Dale, E.S. Umstott, N.

Chiamori and G.E. 0

Abraham, Postmenopausal steroid replacement with micronized dehydroepiandrosterone: preliminary oral bioavailability and dose proportionality studies, Am. J. Obstet. Gynecol. 166 (1992), p. 1163-1168 discussion 1168-1170. 0

Chlebowski, R.T., S.L. Hendrix, et al. (2003). "Influence of estrogen plus progestin on breast cancer and mammography in healthy oy AY postmenopausal women: the Women's Health Initiative Randomized Trial."

Jama 289(24): 3243-53.

D.L. Coleman, E.H. Leiter and R.W. Schwizer, Therapeutic Effects of Dehydroepiandrosterone (DHEA) in Diabetic Mice, Diabetes 31 (1982), pp. 830-833. Colditz, 6.A., K.M. Egn, et al. (1993). “Hormone replacement© thrapy and ricks of breast cancer: results from epidemiologic studies.” Am.

J. Obstet. Gynecol. 168: 1473-1480.

Colditz, G.A., S.E. Hankinson, et al. (1995). “The use of estrogens and progestins and the risk of breast cancer in postmenopausal women.” N.

Engl. J.Med. 332: 1589-1593. 1.

Collaborative Group on Hormonal Factors in Breast Cancer (1997). “Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer.” Lancet 350(9084): 1047-59. 10

Corrao, G., A. Zambon, et al. (2008). “Menopause hormone replacement therapy and cancer risk: an Italian record linkage investigation.” Ann

Oncol 19(1): 150-5.

Coughlin, 5. S., A. Giustozzi, et al. (2000). “A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer.” J Clin Y.

Epidemiol 53(4): 367-75.

Deutsch, S., R. Ossowski, et al. (1981). Comparison between the degree of systemic absorption of vaginally and orally administered estrogens at oy AY

_ \ For different dose levels in postmenopausal women.” Am J Obstet Gynecol 139(8): 967-8.

Dew, J.E., B.G. Wren, et al. (2003). “A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer.”

Climacteric 6(1): 45-52. ©

P. Diamond, L. Cusan, J.L. Gomez, A. Belanger and F. Labrie, Metabolic effects of 12-month percutaneous DHEA replacement therapy in postmenopausal women, J.

Endocrinol. 150 (1996), p. S43-S50.

Dugal, R., K. Hesla, et al. (2000). Comparison of the usefulness of estradiol 0 vaginal tablets and estriol vagitories for the treatment of vaginal atrophy. Acta

Obstet Gynecology Scand 79(4): 293-17.

Englund, D.E. and E.D. Johansson (1978). “Plasma levels of oestrone, oestradiol and gonadotrophins in postmenopausal women after oral and Yo vaginal administration of conjugated equine oestrogens (Premarin).” Br J

Obstet Gynaecol 85(12): 957-64.

Fallowfield, L., D. Cella, et al. (2004). Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC)

Adjuvant Breast Cancer Trial." J Clin Oncol 22(21): 4261-71.0.

Feeley, K.M. and M. Wells (2001). Hormone replacement therapy and the endometrium. J Clin Pathol 54(6): 435-40. oy AY

_ \ M Furuhjelm, M., E. Karlgren, et al. (1980). 'Intravaginal administration of conjugated estrogens in premenopausal and postmenopausal women.' Int

J Gynaecol Obstet 17(4): 335-9.

Galhardo, C.L., J.M. Soares, Jr., et al. (2006). “Estrogen effects on the vaginal pH, flora and cytology in late postmenopause after a long period without hormone therapy.” Clin Exp Obstet Gynecol 33(2): 85-9.

Gambrell, R.D., and F.M. Massey, et al. (1980). 'Use of the progestogen challenge test to reduce the risk of endometrial cancer.'

Obstet Gynecol 55(6): 732-8. 0

Garg, P.P., K. Kerlikowske, et al. (1998). “Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis.” Obstet

Gynecol 92(3): 472-9.

Grady, D., T. Gebretsadik, et al. (1995). “Hormone replacement therapy and endometrial cancer risk: a meta-analysis.” Obstet Gynecol 85(2): 10 304-13.

Gupta, P., 8. Ozel, et al. (2008). “The effect of transdermal and vaginal estrogen therapy on markers of postmenopausal estrogen status.”

Menopause 15(1): 94-7.

Holmberg, A. and H. Anderson (2004). “HABITS (hormonal replacement ~~ 0 therapy after breast cancer—is it safe?), a randomized comparison: trial stopped.” Lancet 363(9407): 453-5.oy AY

_\q—_

Holmberg, L., O.E. Iversen, et al. (2008). “Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.” J Natl

Cancer Inst 100(7): 475-82.

Holmgren, P.A., M. Lindskog, et al. (1989). “Vaginal rings for continuous low-dose release of oestradiol in the treatment of urogenic atrophy.” ©

Maturitas 11(1): 55-63.

Halley, 5.B. (2002). 'Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and estrogen /progestin replacement study follow-up (HERS II).' JAMA 288:58-66.10

Jick, 5. 5. A.M. Walker, et al. (1993). "Estrogens, progesterone, and endometrial cancer." Epidemiology 4(1): 20-4.

C.C. Johnston Jr., S.L. Hui, R.M. Witt, R. Appledorn, R.S. Baker and C.

Longcope, early menopausal changes in bone mass and sex steroids, J.

Clean. Endocrinol. Metab. 61 (1985), 0 pp. 905-911.

D.W.A. Hum, A. Belanger, E. Levesque, O. Barbier, M. Beaulieu, C. Albert,

M. Vallee, C. Guillemette, A. Tchernof, D. Turgeon and S. Dubois,

Characterization of UDP-glucuronosyltransferases active on steroid hormones, J. Steroid Biochem. Mol. Biol. 69 0 (1999), p. 413-423. oy AY

_ \ «=

H. Kawano, H. Yasue, A. Kitagawa, N. Hirai, T. Yoshida, H. Soejima, S.

Miyamoto, M. Nakano and H. Ogawa, Dehydroepiandrosterone supplementation improves endothelial function and insulin sensitivity in men, J. Clin. Endocrinol. Metab. 88 (2003), p. 3190-3195. ©

Kendall, A., M. Dowsett, et al. (2006). Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol 17(4): 584-7.

Kvorning, J.D.N. and H.K. Jensen (1986). Pharmaceutical development of lose—dose estradiol vagitories. International Workshop, 0

Copenhagen.

Labrie, C., A. Belanger, et al. (1988). Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate.

Endocrinology 123: 1412-1417.

Labrie, F. (1991). "Intracrinology." Mol. Cell. Endocrinol. 78: C113-C118. 0

F. Labrie, Future perspectives of SERMs used alone and in combination with DHEA, Endocr. Relat. Cancer 13 (2006), p. 335-355.

Labrie, F. (2007). Wen“Insight: breast cancer prevention and tissue - targeted hormone replacement therapy.” nature Clinical Practice,

Endocrinology & Metabolism 3(8): 584593. 0

F. Labrie, A. Belanger, J. Simard, V. Luu-The and C. Labrie, DHEA and peripheral androgen and estrogen formation: intracrinology, Ann. N.Y.

Acad. Sci. 774 (1995), p. oy AY

_ \ \ —_ 16-28.

Labrie, F., A. Belanger, et al. (2007). “Metabolism of DHEA in postmenopausal women following percutaneous administration.” J Steroid

Biochem Mol Biol 103(2): 178-88.

Labrie, F., A. Belanger, et al. (2007) "Bioavailability and metabolism of 0 oral and percutaneous dehydroepiandrosterone in postmenopausal women" J Steroid Biochem Mol Biol. Oct;107(1-2):57-69..

Labrie, F., A. Belanger, et al. (2006). Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women.

Journal Ster Biochem & Mol Biol 99:0 182-188.

Labrie, F., A. Belanger, et al. (2005). 'GnRH agonists in the treatment of prostate cancer.' Endocrine Reviews 26(3): 361-379.

Labrie, F., A. Belanger, et al. (1997). Marked decline in serum concentrations of adrenaline C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 82: 2396 — 2402.

Labrie, F., A. Belanger, et al. (2007a). "Bioavailability and metabolism of oral and percutaneous dehydroepiandrosterone in postmenopausal women." J Steroid Biochem Mol Biol 107(1-2): 57-69. 0

F. Labrie, A. Belanger, P. Belanger, R. Berube, C. Martel, L. Cusan, J.

Gomez, B. Candas, V. Chaussade, |. Castiel, C. Deloche and J. Leclaire, oy AY

_ \ \ —_

Metabolism of DHEA in postmenopausal women following percutaneous administration, J. Steroid Biochem. Mol.

Biol. 103 (2) (2007b), p. 178-188.

Labrie, F., Cusan, et al. (2008). Effect of Intravaginal DHEA on Serum

DHEA and Eleven of its Metabolites in Postmenopausal Women." Journal e Sterling Biochem & Mol Biol: In press.

Labrie, F., Cusan, et al. (2008). Effect of One-Week Treatment with

Vaginal Estrogen Preparations on Serum Estrogen Levels in

Postmenopausal Women.” Menopause In press.

Labrie, F., L. Cusan, et al. (2008). “Changes in serum DHEA and eleven 0 of its metabolites during 12-0001 percutaneous administration of DHEA.”

J Steroid Biochem Mol Biol 110(1-2): 1-9.

Labrie, F., P. Diamond, et al. (1997). ‘Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women.

Labrie, F., A. Dupont, et al. (1985). Complete androgen blockade for the treatment of prostate cancer. Important Advances in Oncology. V.T.de

Vita, S. Hellman and 5. A. Rosenberg. Philadelphia, J.B. Lippincott: 193- 217. 0

F. Labrie, V. Luu-The, S.X. Lin, C. Labrie, J. Simard, R. Breton and A.

Belanger, The Key Role of 17p--HSDs in Sex Steroid Biology, Steroids 62 (1997), pp. 148-158. oy AY

S.©, Lalmata, Labrie, V. Luu-The, S.-X. Lin, J. Simard, C. Labrie, M. Pelletier and A. Belanger, Intracrinology: role of the family of 175-hydroxysteroid dehydrogenases in human physiology and disease, J. Mol. Endocrinol. 25 (2000), p. 1-16. Labrie, F., V. Luu-The, et al. (2005). "ls DHEA a hormone? Starling Review." J Endocrinol 187:169-196. 0

Labrie, F., V. Luu-The, et al. (2003). Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocrine

Reviews 24(2): 152-182.

Labrie, F., V. Luu-The, et al. (20006). Dehydroepiandrosterone (DHEA) is 00 an anabolic steroid like dihydrotestosterone (DHT), the most potent natural androgen, and tetrahydrogestrinone (THG). J Steroid Biochem Mol Biol 100(1-3):52-8.

F. Labrie, J. Simard, V. Luu-The, A. Belanger, G. Pelletier, Y. Morel, F.

Mebarki, R. Sanchez, F. Durocher, C. Turgeon, Y. Labrie, E. Rheaume, Vo.

C. Labrie and Y. Lachance, The 3*-hydroxysteroid dehydrogenase/isomerase gene family: lessons from type 11 3(3-HSD congenital deficiency. In: V. Hansson, F.O. Levy and K. Tasken, editors,

Signal Transduction in Testicular Cells. Ernst Schering Research

Foundation Workshop, vol Suppl. 2, Springer-Verlag, Berlin (1996), p. 00 185-218.

Labrie, J. Simard, V. Luu-The, A. Belanger and G. Pelletier, structure, function and tissue-specific gene expression of 3*-hydroxysteroid oY AY

_ \ ¢ —_ dehydrogenase/5-ene-4-ene isomerase enzymes in classical and peripheral intracrine steroidogenic tissues, J. Steroid

Biochem. Mol. Biol. 43 (1992), p. 805-826.

F. Labrie, R. Poulin, J. Simard, V. Luu-The, C. Labrie and A. Belanger,

Androgens, DHEA and breast cancer. In: T. Gelfand, Editor, Androgens © and Reproductive Aging, Taylor and Francis, Oxsfordshire, UK (2006), 00. 113-135.

Labrie, Y. Sugimoto, V. Luu-The, J. Simard, Y. Lachance, D. Bachvarov, ©. Leblanc, F. Durocher and N. Paquet, Structure of human type Il 5* - reductase, Endocrinology 131 0 (1992), pp. 1571-1573.

Y. Labrie, F. Durocher, Y. Lachance, C. Turgeon, J. Simard, C. Labrie and F. Labrie, The human type Il 17*-hydroxysteroid dehydrogenase gene encodes two alternatively — spliced messenger RNA species, DNA Cell Biol . 14 (1995), p. 849-861. 0

Lacey, J.V., P.J. Mink, et al. (2002). “Menopausal hormone replacement therapy and risk of ovarian cancer.” JAMA 288: 334-341.

Li, L., 5. J. Plummer, et al. (2008). “A common 8924 variant and the risk of colon cancer: a population-based case-control study.” Cancer

Epidemiol Biomarkers Prev 17(2): 33942. 0

C.H. Liu, G.A. Laughlin, U.G. Fischer and S.S. Yen, Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in oy AY

A _ _ postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity, J. Clin. Endocrinol. Metab. 71 (1990), p. 900-906.

Long, C.Y., C.M. Liu, et al. (2006). "A randomized comparative study of the effects of oral and topical estrogen therapy on the vaginal © vascularization and sex-balance function in hysterectomized postmenopausal women." Menopause 13(5): 737-43.

V. Luu-The, 01 Dufort, N. Paquet, 6. Reimnitz and F. Labrie, Structural characterization and expression of the human dehydroepiandrosterone sulfotransferase gene, DNA Cell 0

Biol. 14 (1995), p. 511-518.

V. Luu-The, Y. Zhang, N. Poirier and F. Labrie, Characteristics of human types 1, 2 and 3 17*-hydroxysteroid dehydrogenase activities: oxidation - reduction and inhibition, J. Steroid Biochem. Mol. Biol. 55 (1995), p. 581-58 10

Lyytinen, H., E. Pukkala, et al. (2006). "Breast cancer risk in postmenopausal women using estrogen-only therapy." Obstet Gynecol 108(6): 1354-60.

E.G. MacEwen and |.D. Kurzman, Obesity in the dog: role of the adrenal steroid dehydroepiandrosterone (DHEA), J. Nutr. 121 (1991), p. 551- 0

S55. Mandel, F.P., F.L. Geola, et al. (1983). Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 57(1): 133-9. oy AY

_ \ a _

Manonai, J., U. Theppisai, et al. (2001). “The effect of estradiol vaginal tablet and conjugated estrogen cream on urogenital symptoms in postmenopausal women: a comparative study.” J Obstet Gynaecol Res 27(5): 255-60.

Martin, P., Ma S. 5. Yen, et al. (1979). "Systemic absorption and sustained effects of vaginal estrogen creams." Jama 242(24): 2699-700.

Marx, P., G. Schade, et al. (2004). "Low-dose (0.3 mg) synthetic conjugated estrogens A is effective for managing atrophic vaginitis."

Maturitas 47(1): 47-54.

Mattson, L.A., G. Culberg, et al. (1989). Vaginal administration of low 0 dose estradiol-effects on endometrium and vaginal cytology. Maturitas 11: 217-222.

R.B. Mazess, On aging bone loss, Clin. Orthop. 165 (1982), p. 239- 252. Meisels, A. (1967). "The maturation value." Acta Cytol 11:249.

Mertens, H.J., M.J. Heineman, et al. (1996). Androgen receptor 10 content in human endometrium. Eur J Obstet Gynecol Reprod Biol 70(1):11-3.

Mettler, A. and P. 6. Olsen (1991). "Long-term treatment of atrophic vaginitis with low-dose oestradiol vaginal tablets." Maturitas 14(1): 23-31.

C.J. Migeon, A.R. Keller, B. Lawrence and T.H. Shepart...aaa 0

Dehydroepiandrosterone and androsterone levels in human plasma. Effect of age and sex: day-to-day and daily variations, J. Clin. Endocrinol.

Metab. 17 (1957), p. 1051-1062. oy AY

A.J. Morales, J.J. Nolan, J.C. Nelson and 5.5. Yen, Effects of replacing a dose of dehydroepiandrosterone in men and women of advancing age, J. Clin. Endocrinol.

Metab. 78 (1994), p. 1360-1367.

Morales, L., P. Neven, et al. (2004). “Acute effects of tamoxifen and 0 third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients.” Anticancer Drugs 15(8): 753-60.

N.A.M.S. (2007). Position Statement of the North American Menopause

Society.” Menopause 14: 357-69.

Nachtigall, A. E. (1995). Clinical trial of the estradiol vaginal ring in the 0

U.S." Maturitas 22 Suppl: S43-7.

Naessen, T., K. Rodriguez-Macias, et al. (2001). “Serum lipid profile improved by ultra-low doses of 17 beta-estradiol in elderly women.” J

Clin Endocrinol Metab 86(6): 275762.

Nelson, H.D., K. A. Vesco, et al. (2006). 'Nonhormonal therapies for 0 menopausal hot flashes: systematic review and meta-analysis." Jama 295(17): 2057-71.

J.E. Nestler, C.O. Barlascini, J.N. Clore and W.G. blackard,

Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men, J. Clin. 0

Endocrinol. Metab. 66 (1988), p. 57-61. Nilsson, K. and G. Heimer (1992). Low-dose oestradiol in the treatment of urogenital oestrogen deficiency—a pharmacokinetic and pharmacodynamic study. Maturitas oy AY

15(2): 121-7.

Notelovitz, M., 5. Funk, et al. (2002). Estradiol absorption from vaginal tablets in postmenopausal women. Obstet Gynecol 99(4): 556-62.

Orentreich, N., J.L. Brind, et al. (1984). “Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations © throughout adulthood.” J.Clin. Endocrinol. Metab. 59: 551-555.

Pandit, A. and J. 6. Ouslander (1997). Postmenopausal vaginal atrophy and atrophic vaginitis. Am J Med Sci 314(4): 228-31.

Persson, I., H.O. Adami, et al. (1989). "Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: 0 results of a prospective study." Bmj 298(6667): 147-51.

Ponzone, R., N. Biglia, et al. (2005). Vaginal oestrogen therapy after breast cancer: is it safe? Eur J Cancer 41(17): 2673-81.

Rigg, A. A., H. Hermann, et al. (1978). Absorption of estrogens from vaginal creams. N Engl J Med 298(4): 195-7. 'eo

B.L. Riggs, HW. Wahner, W.L. Dunn, R.B. Mazess, K.P. Offord and

L.J. Melton,

Differential changes in bone mineral density of the appendicular and axial skeleton with aging: relationship to spinal osteoporosis, J. Clin. Invest. 67 (1981), p. 328-335. 0

SNAY

_\q—_

Riman, T., P. W. Dickman, et al. (2002). “Hormone replacement therapy and the risk of invasive epithelial ovarian cacner in Swedish women.” J

Natl Cancer Inst 94:497-504.

Rinaldi, S., H. Dechaud, et al. (2001). 'Reliability and validity of commercially available, direct radioimmunoassays for measurement of 0 blood androgens and estrogens in postmenopausal women.'

Epidemiol Biomarkers Prev 10(7): 757-65.

Rioux, J.E., C. Devlin, et al. (2000). "7 beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis." Menopause 0 7(3): 156-61.

Rodriguez, C., A.V. Patel, et al. (2002). "Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women."

JAMA 285: 1460-1465.

Rosenberg, A. U., C. Magnusson, et al. (2006). ‘Menopausal hormone 10 therapy and other breast cancer risk factors in relation to the risk of different histological subtypes of breast cancer: a case-control study.’

Breast Cancer Res §(1): R11.

Rossouw, J.E., G.L. Anderson, et al. (2002). 'Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal 0 results From the Women's Health Initiative randomized controlled trial.'

Jama 288(3): 321-33. oy AY

=« As Salminen, H.

S., M.

E.

Saaf, et al. (2007). “The effect of transvaginal estradiol on bone in aged women: a randomized controlled trial.” Maturitas .370-81:57(4) Tulchinsky, et al. (1977). “Vaginal absorption of estrone and L. Schiff, 00, 17beta—estradiol.” Fertil Steril 28(10): 1063 -6 © Schmidt, G., 5. B.

Andersson, et al. (1994). 'Release of 17-beta- oestradiol from a vaginal ring in postmenopausal women: pharmacokinetic evaluation.' Gynecol Obstet Invest.253-60:38(4) E.D.

Schriock, C.K.

Buffington, G.D.

Hubert, B.R.

Kurtz, A.E.

Kitabchi, 01 J.E.

Buster and J.R.

Givens, divergent correlations of circulating dehydroepiandrosterone sulfate and testosterone with insulin levels and insulin receptor binding, J. Clin.

Endocrinol.

Metab. p.p. 1329-1331. 0 (1988) 66 Sillero—-Arenas, M., M.

Delgado--Rodriguez, et al. (1992). “Menopausal hormone replacement therapy and breast cancer: a meta-analysis.” Obstet.

Gynecol. 79: 286-294. Z.

Reape, et al. (2007). "Randomized, multicenter, A. Simon, J.

A., double-blind, placebo—controlled trial to evaluate the efficacy and safety of 0 synthetic conjugated estrogens B for the treatment of vulvovaginal atrophy in healty postmenopausal women." Fertil Steril In press. oy AY ‏

_- \ so

E.R. Simpson, Role of aromatase in sex steroid action, J. Mol.

Endocrinol. 25 (2000), pp- 149-156.

Simunic, V., 01 Banovic, et al. (2003). “Local estrogen treatment in patients with urogenic symptoms.” Int J Gynaecol Obstet 82(2): 187-97. ©

Smith, D.C., R. Prentice, et al. (1975). “Association of exogenous estrogen and endometrial carcinoma.” N. Engl. J.Med. 293: 1164-1167.

Smith, P., G. Heimer, et al. (1993). Oestradiol -releasing vaginal ring for postmenopausal urogenital atrophy. Maturitas 16(2): 145-54,000

Sourla, A., M. Flamand, et al. (1998). Effect of dehydroepiandrosterone on vaginal and uterine histomorphology in the rat. J. Steroid Biochem.

Mol. Biol. 66(3): 137-149.

Steinberg, H. K., 5. B. Thacker, et al. (1991). “A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer.” 10

JAMA 265: 1985-1990.

K.K. Steinberg, L.W. Freni-Titulaer, E.G. DePuey, D.T. Miller, D.S.

Sgoutas, C.H. Coralli, D.L. Phillips, T.N. Rogers and R.V. Clark, sex steroids and bone density in premenopausal and perimenopausal women,

J.Clin. Endocrinol. Metab. 69 (1989), p. 533-539. 00

Suckling, J., A. Lethaby, et al. (2006). "Local oestrogen for vaginal atrophy in postmenopausal women." Cochrane Database System Rev 18(4): CDO01500. oy AY

_— \ As Swanson, M. Lorentzon, L. Vandenput, D. Mellstrom, F. Labrie, A. Rane, J. Jakobsson, C. Ohlsson, UGT2B7 H268Y polymorphism is associated with serum sex steroid levels and cortical bone size in young adult men, JCEM (2007), in press. Prud'homme, S. 0.na Tchernof, J.P. Despres, A. Belanger, A. Dupont,

Moorjani, P.J. Lupien and F. Labrie, Reduced testosterone and adrenaline

C19 steroid levels in obese men, Metabolism 44 (1995), pp. 513-519.

Turgeon, J.S. Carrier, E. Levesque, D.W. Hum and A. Belanger, relative enzymatic activity, protein stability, and tissue distribution of human steroid—metabolizing 6128 no subfamily members, Endocrinology 142 0 (2001), pp. 778-1781.

Utian, W.H., L. Shoupe, et al. (2001). 'Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate.' Fertil Steril 75(6): 1065-79.

Vermeulen and A. Verdonck, Radioimmunoassays of 17p—hydroxy-5*- Yo androstan—-3-one, 4-androstene-3,17-dione, dehydroepiandrosterone, 17*-hydroxyprogesterone and progesterone and its application to human male plasma , J. Steroid Biochem. 7 (1976), p. 1-10.

D.T. Villareal and J.O. Holloszy, effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial, 0

JAMA 292 (2004), p. 22432248.

Voigt, L.F., N.S. Weiss, et al. (1991). “Progestagen supplementation of exogenous oestrogens and risk of endometrial cancer.” Lancet 338(8762): 274-17. oy AY pp

Weisberg, E., R. Ayton, et al. (2005). Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet. Climacteric 8(1): 83-92.

Wied, G.L. (1993). Industrial developments in automated cytology as submitted by their developers. Anal Quant Cytol Histol 15(5): 358-70 ©

Wines, N. and E. Willsteed (2001). "Menopause and the skin." Australas J

Dermatol 42(3): 149-8; quiz159.

Zang, H., Sahlin, et al. (2007). “Effects of testosterone treatment on endometrial proliferation in postmenopausal women.” J Clin Endocrinol

Metab 92(6): 2169-75. B. Zumoff, G.W. Strain, L.K. Miller and W. 0

Rosner, Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women, J. Clin. Endocrinol.

Metab. 80 (1995), p. 1429-1430. Sal Vaginal dryness in 775 postmenopausal women 10 0051016000852 (Wines and Willsteed 2001; N.A.M.S.) (2007) exists for many reasons, especially fear of complications from €SIrogens. vaginal atrophy seeks 775 women with symptoms of vaginal atrophy 00 for medical treatment (2007) (Pandit and Ouslander 1997; N.A.M.S.) so there is clear medical significance and a great opportunity to improve the lives of a large group of women who suffer 0 Vaginal atrophy (sal) is very old. and agitation, cvaginal dryness Sas increases over time if not treated. a

_ Based on the well-known fact that the secretion of estrogen through the ovaries stops at Uadil 016070081156; Nevertheless, systemic, topical, and topical estrogens have so far been the only means of treating vaginal atrophy; It has been proven that systemic estrogens, + systemic and local estrogens, estrogens alone, estrogens + progestin (HRT) ©: breast cancer, increase the risk of developing breast cancer (ERT). ) Steinberg, Thackeret 80. 1991; Sillero—Arenas, Delgado-Rodriguez et al. 1992; Colditz, Egn et al. 1993; Colditz, Hankinson et al. 1995; Collaborative Group on Hormonal Factors in Breast Cancer 1997; Hulley 2002, Beral 2003, Chlebowski, Hendrix et al. 2003, Holmberg and Anderson 2004, Lyytinen, Pukkala et al. 2006, Corrao, Zambon et al. 2008, Holmberg, Iversen et al. 2008, Li, Plummer et al. al. 2008) ovarian cancer and ovarian cancer (Garg, Kerlikowske et al. 1998; Coughlin, Giustozzi et al. 2000; Lacey,

Mink et al. 2002; Riman, Dickman et al. 2002; Rodriguez, Patel et al. D 2002; Rossouw, Anderson et al. 2002; Lyytinen, Pukkala et al. 2006). Likewise, endometrial cancer endometrium (estrogens alone): (Gambrell, Massey et al. 1980; Persson, Adami et al. 1989; Voigt, Weiss et al. 1991; Jick, Walker et al. 1993; Grady, Gebretsadik et al. 1995; 0 Beral, Bull et al. 2005). The awareness raising that followed the preliminary study on women's health was as follows: a

The Women's Health Initiative Study (Rossouw, Anderson et al. 2002) had the greatest effect in raising doubts about the safety of available treatments for menopausal symptoms (Archer 2007). Although intravaginal formulations have been developed to avoid systemic exposure to hormones systemic exposure estrogens Several studies agree that all formulations of estrogen administered intravaginally lead to relatively high estrogen levels in serum measured directly or through their systemic effects: Englund and Johansson 1978; Rigg, Hermann et al. 1978; Martin, Yen et al. 1979; Furuhjelm, Karlgren et al. 1980; Deutsch, Ossowski et al. 1981; Mandel, Geola et al. 1983; Nilsson and Heimer 1992; Nachtigall 1995;

Ayton, Darling et al. 1996; Dugal, Hesla et al. 2000; Rioux, Devlin et al. 0 2000; Manonai, Theppisai et al. 2001; Notelovitz, Funk et al. 2002;

Ponzone, Biglia et al. 2005; Weisberg, Ayton et al. 2005; galhardo,

Soares et al. 2006; Kendall, Dowsett et al. 2006; Long, Liu et al. 2006;

Bachmann, Lobo et al. 2008. Yo These data showing significant Sal in serum estrogen levels in clear SLE suggest that the use of estrogen formulations given vaginally as Lal is likely to be associated with an increased risk of breast and uterine cancer. Kvorning and Jensen 1986; Mattson, Culberg et al. 1989; Rosenberg, Magnusson et al. 2006; N.A.M.S. 2007. Formal concerns have arisen about the anabolic effects of vaginal estrogen formulations (YL - (N.A.M.S. 2007)) endometrium as) on the lining of post-(E2) serum estradiol in relation to most previous measurements of serum estradiol levels. To administer estrogen hormones within radioimmunoassays, radioimmunoassays, a technique that lacks specificity; accuracy; Reliability and sensitivity, dintravaginal vagina, no

Ld (Rinaldi, Dechaud et al. 2001) measured estrogen hormones in serum 5 using GLP-validated mass spectrometry assays after administration of the two most widely used formulations Inside the vagina Cusan et al. 2008), 2516a). This study explicitly demonstrates that 3S from an E2 nanoparticle (E2 Yo) 2g/day) and conjugated estrogen cream (1g of 6175©mg of conjugated estrogens) (and) after 1 week of daily administration They lead to an increase of about * times the serum E2 in women of postmenopausal age These data indicate that the effects of estrogens that are placed topically in the vagina are likely to be limited to it, and the systemic effect is as previously expected: Englund and Johansson 1978; Rigg, Hermann et al. 1978; Martin, Yen et al. 1979; Furuhjelm, Karlgren et al. 1980; Deutsch, Ossowski et al. 1981; Mandel, Geola et al. 1983; Nilsson and Heimer 1992; Nachtigall 1995; Ayton, Darling et al. 1996; Dugal, Hesla et al. 2000; Rioux, Devlin et al. Manonai, Theppisai et al. 2001; Notelovitz, Funk et al. 2002; 2000; Ponzone, Biglia et al. 2005, Weisberg, Ayton et al. 2005, Galhardo, Vo, Soares et al. 2006, Kendall, Dowsett et al. 2006, Long, Liu et al. 2006, Bachmann, Lobo et al. al. 2008. In addition to previous concerns regarding Evidence of safety around estrogen hormones that are given lea and topically; Recent data clearly indicate that women not only suffer from a deficiency of Ye hormones, estrogens, at the time of menopause, but rather that they are deprived of Laila in the early thirties; Many androgens construct specific peripheral target tissues by converting dehydroepiandrosterone (DHEA) into androgens and/or estrogens: Labrie, Belanger et al. 1988; Labrie 1991; Labrie, Luu-The et al. 2003; 2005. Yo SY AY

In fact, serum DHEA and DHEA sulfate continuously lead to a decrease in the peak observed at the age of 30:

Orentreich, Brind et al. 1984; Labrie, Belanger et al. 1997; Labrie, Luu (The et al. 2003 -) to a value that decreases by 750 at the time of menopause (Labrie, Luu) (© Led menopause Belanger et al. 2006). (The role of androgens in ald) It is important to mention that shal secretes an amount of androgens up to 0:75 as seen in men: DHEA (Labrie, Belanger et al. 1997; Labrie, Luu-The et al. 2005) Serum is the predominant source of predominant source androgens that play a number of 0 physiological roles in women: DHEA 17560, the decrease by (Labrie, Luu-The etal. 2003; Labrie 2007) found vertigo Already at the time of menopause, it leads to a similar decrease by 7760 of the total androgen concentration (Labrie, Belanger et al. 2006), which leads to possible signs and symptoms (adil androgen hypoandrogenicity in bone and muscle). 6a00150; skin 610a5; cmammary gland all, vagina 789108, brain, and the effect also on metabolite glucose, insulin, and lipid (Labrie, Luu-The et al. 2003; Labrie 2007) from B Androgen target tissues Recent data have shown that the vagina is sensitive to androgens 0 after administration of DHEA in a rat; Where it has beneficial effects; Not only on the superficial epithelial layer of the vagina, but also on the collagen fibers of the propria muscle (Berger, El-Alfy et al. 2005). Based on data confirmed by clinical studies:

(Labrie, Diamond et al. 1997; Labrie, 00580 et al. 2008) and preclinical (Sourla, Flamand et al. 1998; Berger, EI-Alfy et al. 2005) studies that demonstrate beneficial effects on vaginally to DHEA given transdermally or topically; The current Luh clinical trial is proactive; randomized, drug-satisfactory placebo-controlled effect of three doses of DHEA given daily intravaginally for 11 weeks based on changes in surface WAY

and parabasal ¢ and vaginal pH and most symptoms of vaginal atrophy (ale) as the main purposes. The data (AN) are clear that DHEA administered topically is very effective and rapid in the correction of BE signs and symptoms of vaginal atrophy; Where the effect is close to the maximum after two weeks of administration of DHEA deja, no significant changes occur in

0 estrogens or androgens in the serum, while all the other 0 remain constant or remain in the proportions found in the normal shall that no longer menstruates. When DHEA is administered topically in Gam vagina Jed) the suid effects of hormones 05 and 80010961 in the vagina without significant release of estradiol or testosterone into the blood:

Ster.

Biochem.

Mol.

Biol.

In press) Yo. L. (Labrie, Cusan et al.) When the formation of androgens and/or estrogens from DHEA according to the syntracrinology process, no tissue response is expected because the response depends on The activity of the enzymatic activity present in particular in each cell of the tissue. Thus, it cannot be expected from the hormones estrogen and androgens that are produced from DHEA in a single tissue;

0 . The extent to which similar androgens and estrogen hormones are produced in another tissue. Clinical trial results 40-210 (Example 0) demonstrate that for the first time, local administration of DHEA as hormone precursor replacement therapy (HPRT) is highly vlad and rapid. in a calendar

oYAY

And the*

(abel) and signs of vaginal atrophy in postmenopausal women

session.

More importantly, this can be achieved at a dose (70.5) of DHEA that does not lead to an increase in blood levels.

Active estrogens or androgens in serum without any change in serum DHEA.

© or unchanged; While any metabolites remain in the ratios found in normal women

(Labrie, Cusan et al. 2008) who no longer menstruate

Although 7975 women of postmenopausal age suffered from atrophy

Vaginal atrophy “(Wines and Willsteed 2001; N.A.M.S. 2007) therefore

Their quality of life is affected during 5,558 terminations, but only 770 seek treatment (Pandit and o) Ouslander 1997 | 0 This is primarily due to fear of breast cancer

blood levels of breast cancer associated with increased levels of estrogen hormones in the blood

.estrogens and because the secretion of estrogen in the systemic cycle is exclusively associated with the ovaries

5 and it is interrupted by the cessation of menstruation » However, giving estrogens to women who are in menopause

Age after menopause does not seem normal from a physiological point of view. After WHI, the scientific challenge is to explore the types of hormonal replacement therapy 811611181176 and the formulas that give

All the advantages of interrupting the cycle of estrogens, along with an improvement in their quality of life; and reduce

risks are minimized and benefits are maximized (Archer 2007)

Does not depend on estrogen. Delat has not been proven convincing

(Nelson, Vesco et al. 2006; Suckling, Lethaby et al. 2006) However, the 00 women and their physicians are not aware of any safe treatment for vaginal atrophy.

Hua, many of the estrogens, are known to be an effective treatment for vulvar and vaginal atrophy.

Pandit and Ouslander 1997; Utian, Shoupe et al. (vulvovaginal atrophy

1. actually; The transvaginal E2 tablet has been shown to be as effective as the ring

,: E2

Bad

m (Weisberg, Ayton et al. 2005) and mS conjugated estrogens Rioux, Devlin et al. 2000; Manonai, Theppisai et al. (estrogen cream 2001). This new HPRT differs by an increase of ∼1 times E23 from serum E23 according to mass spectrometry after treatment with intravaginal E2 or conjugated estrogens Cusan et al. 2008 ), 85116a). These recent data through changes in serum estrogens from a wide range of studies confirm that all estrogen formulations administered intravaginally lead to elevated serum estrogen concentrations as measured by radioimmunoassays or through their systemic effects: Englund and Johansson 1978; Rigg, Hermann et al. 1978; Martin, Yen et al. 1979; Furuhjelm, Karlgren et al. 1980; Deutsch, Ossowski et al. 1981; 1983; Nilsson and Heimer 1992; Nachtigall 1995; Ayton, Darling et al. 1996; Dugal, Hesla et al. 2000; Rioux, Devlin et al. Manonai, Theppisai et al. 2001; Notelovitz, Funk et al. 2002; 2005; Weisberg, Ayton et al. 2005; Galhardo, Vo Soares et al. 2006; Kendall, Dowsett et al. 2006; Long, Liu et al. 2006; 2008. The most frequently reported duel with vaginal estrogens is vaginal bleeding and breast gal pain that are secondary to increased serum estrogens (2006 -) Suckling, Lethaby et al. These side effects have been reported for the Loop 2], conjugated estrogen cream and tablet (Ayton, Darling et al. 1996; Weisberg, Ayton et al. 2005) 2 In light of the above, there are concerns Also on the stimulating effects of vaginal estrogens on the lining of the uterus (N.A.M.S. 2007) endometrium. Uterine bleeding, breast pain ill 8, and perineal pain were reported in 795 women taking SN vaginal tablets. AY

For YE weeks lay two ATEs complained of the same symptoms in the vaginal GHA estrogen cream group (2000) (Rioux, Devlin et al. 2006) not mentioned (Suckling, Lethaby et al.

A difference between different vaginal estrogen preparations. It is known that atrophic vaginitis in women of postmenopausal age may be aggravated or induced by the use of aromatase inhibitors for the treatment of breast cancer 556851. In fact, there are benefits to these drugs in the treatment of breast cancer. breast by decreasing L2 biosynthesis in all tissues; And then an increase in the frequency and severity of menopausal symptoms (Fallowfield, Cella et al. 2004; Morales, Neven et al. 4. In a recent study in which seven women with breast cancer were treated with Vagifem, which contains an aromatase inhibitor at a dose of daily Yo of 2 micrograms daily for 2 weeks and then twice weekly; serum ratio increased from an average of 2 picomoles/l to VY picomoles/l over 2 weeks (range ? to 777) (2006) (Kendall, Dowsett) serogroup 52 levels generally decreased thereafter to levels of 00 pmol/L or less although serotypes of 1717 and 9517 pmol/L were present in weeks 1-01. In a patient who received AY picomol/L cream at 2 weeks It should be stated that all 52 size samples were taken at the time of the patient visit; a time not comparable to the highest levels of 2 in serum after administration 8916607/. Thus, it is likely that the percentages found in (Kendall, Dowsett et al. 2006) decrease; to an unknown extent; the true elevation of serum E2 after administration of Vagifem tablets or Premarin cream. inside a for a vagina. 0 - The two researchers concluded that Vagifem should not be used with aromatase inhibitors. These results obtained in women with breast cancer treated with aromatase inhibitors raise a serious issue about the use of any estrogen given vaginally, orally, or percutaneously in postmenopausal women. Elevation of serogroup 2 after treatment with various intravaginal estrogen preparations leading to an increased risk of breast cancer is well known (Rosenberg, Magnusson et al., 2006). that study that

to

It involved a small number of events and a short follow-up period (4.7 7 of the subgroup among 077 women) Bi did not appear statistically significant in disease-free living in the subgroup of women who used vaginal estrogens (2003) Dew, Wren et al. It does not seem plausible to increase serum 2 levels during breast cancer treatment when the goal of 0 treatment with aromatase inhibitors is specifically to inhibit the biosynthesis of L52 to the greatest degree. 2; when administered in a dose of 1 microcba it brought the range of serum E2 levels up to 80 pmol/L with values less than 0 pmol/L during 14 and thereafter (1986 and Jensen 6/000109! ). In a more recent study using Vagifem the mean and maximum ae range of serum E2 concentrations were measured during 0-hour YE at VA + 99 pmol/L and 84 pmol/L for the μg Yo dose. while the two values TY + 1 picomole/liter were fey picomoles/liter, respectively; They are present in the dose of 01 micron pall cdf. (Notelovitz, Funk et al. 2002) aha and estrogen creams (533) administered vaginally resulted in higher serum estrogen levels (Schiff, Tulchinsky et al. 1977; Rioux, Devlin et al. 2000) No. using 01 µg and 75 µg of 52 vaginal tablets; Serum 2© has been shown to increase values by about 90 and 60 pmol/L, respectively; From basal values of about VO pmol/L (Nilsson and Heimer 1992) serum E2 containing Vagifem was reported at a maximum plasma concentration of YE + 51 pg/mL per day Cun 10 This value was practically unchanged on days 0 (YY + £V) VE (picg/mL) and 0 (£3 + Su YV) (Vagifem, Physician Package Insert) in 1999. In another study, after 0 weeks of treatment with YO μg of vagifem, serum II levels were shown to remain stable with a range of 70.5 + 0017 pg/mL to 0.9 Su g/mL. Mel (2008) Ka (Bachmann, Lobo et al.) explain this data by stating that it is possible that blood samples were taken after or 7891607 days after delivery. Treatment is likely to be associated with a loss of quality of experiences ON AY

As it depends on the immunity used dua, serum levels of 52, according to mass spectrometry, decrease in women of postmenopausal age by two or more times (Labrie,) (Belanger et al. 2006 in a previous study Oral and vaginal administration of 1.70 mg of Premarin raises serum ©2 and 651006 levels up to at least 100 pg/mL and 1,000 pg/mL, respectively, 1 hour after YE administration, where Levels become somewhat higher after vaginal administration Serum gonadotropin levels were reduced in some cases (Englund and Johansson 1978). reported similar data. In a recent study, after ?months of administration of 6,178 mg of Premarin (orally or intravaginally), serum levels of 52 serum levels increased to 87.1 and 8:71 pg/ml. arrangement (Liu et al., 2000a); Demonstrating systemic exposure ale! is very significantly superior to intravaginal .oral estrogen administration with only 777 serum E2 (serological adds) intravaginally compared to oral .oral conjugated estrogen administration in a VY-continued study weeks using Premarin vaginal cream at a daily dose of two grams, three times weekly, 771 women experienced bleeding after a progestogen test (Nachtigall 1995). Furthermore, 1 of these women showed 5a in cla endometrial thickness according to ultrasonography. echography no increase in serum El, E2 or EIS levels has been reported using the vaginal ring (Nachtigall 1995; Gupta, Ozel et al. 2008) 78910809 00 although a significant increase in 15 E25 was observed in women over 61 years of age (Naessen, Rodriguez-Macias et al. 2001) in the EST episode group. According to a recent study, serum E2 increased from YY + 16 pmol/L to £9 + TE pmol/L per week Vi (Weisberg, Ayton et al. 2005). hand «gyal in m In the Vagifem group, serum E2 Yo rose from YY + 15 pmol/L to 76 + SpO) mol/L. Although ld reported oY AY

— ¢ ¢ — Both researchers found that serum E2 remained the same or approached the values found in a normal woman who no longer menstruated. in week 8; After treatment with an EST loop or Vagifem, 71-777 women complained of enuresis + AYA Ts from urinary urgency jill za and 7-18 from jue sexual intercourse (2005). Weisberg, Ayton et al. All three studies confirmed that the transvaginal E2 loop allows for low serum E2.

During a period of 900 days except for the rise of estrogen in serum which reaches the lower region of the ratio found in normal shal or 001 up to Yoo pmol/ml during hours 1.5 - 8 The first after the insertion of the loop: Holmgren, Lindskog et al. 1989; Schmidt, Andersson et al. 1994

“(Baker and Jaffe 1996) 0 That is, daily administration of E2 in the amount of V.0 μg intravaginally has systemic effects represented in a significant increase in bone mineral density 5006 in total hip bone and lower back after two years of treatment with a vaginal dose of E2 (Salminen, Saaf et al. 2007). In light of the above, there are concerns about the stimulating effects of vaginal estrogens on

Vo endometrium (N.A.M.S. 2007) endometrium after VY weeks of treatment of YY a woman with a dose of 2 micrograms of Yo that Jala (haat) vaginal “(Vagifem) intravaginal” proved to be Lay ge one with simple hyperplasia (Bachmann, Lobo et ) simple hyperplasia (al. 2008) In a one-week YE study of 80 women, there was one case with endometriosis (Rioux, Devlin et al. al. 2000) proliferative endometrium sal).

Yes, and in a study of 91 weeks of study, 91 women; The number of women with endometriosis (gil) was only two (Mettler and Olsen 1991). In an 11-week study using Premarin vaginal cream at a dose of two grams, three times i.e. ged 771 women suffered from Bleeding after the Nachtigall (progestogen) test 7217 of these women showed BAL in olds endometriosis according to ultrasonography. may be

Bad

C ¢ — 1.7 mg of conjugated estrogens given intravaginally; three times a week; to induce proliferation of the endometrium; Unfortunately, rarely; As this was observed in one of the twenty women (Nachtigall-1995), sustained release of the sustained-release estradiol ring (EST) stimulated endometrial proliferation similar to © 17, » mg of Premarin cream (Ayton, Darling et al. 1996) but less than 0.75 mg of Nachtigall (Premarin 1995). ring (est ring) and conjugated estrogen cream (premarin cream stimulates endometrial cell proliferation) 1995; Nachtigall (Ayton, Darling et al. 1996) It was found in two cases of moderate endometrial cell proliferation or hyperplasia of 0 Hyperplasia in the endometrial polyp with a loop ((Nachtigall 1995) E2, while two cases of hyperplasia (one simple and the other complex; without patterns) were evident when using conjugated estrogen cream in the conjugated estrogen cream versus tablet trial. 2] (Rioux, Devlin etal. 2000) The vaginal tablet Led2 has been associated with endometrial hyperplasia in a similar manner to vaginal tableting: (Dugal, 16518 et al. 2000: Manonai, Th. eppisai et al. 2001) 10 but less than conjugated estrogen cream Manonai, Theppisai et al. ( conjugated estrogen cream 2001). Although serum estrogen levels were increased to a lower degree after topical intravaginal application compared to oral or transdermal HRT or ERT, the risk of cancer in Yo was reduced. breast cancer gill is still a problem and there is still doubt about the safety of 017 compounds that hax transvaginally (Suckling, Lethaby et al. 2006; intravaginal (NLALMLS. 2007). Serum 5 is less after vaginal administration compared to oral or skin administration.

— a ¢ —

It is significantly higher than the postmenopausal levels of all estrogen formulations

(Ponzone, Biglia et al. 2005) It is given vaginally

In addition to the increased risk of breast cancer associated with the administration of estrogen compounds

It is important, SS, that the real hormonal difference between women in a period

Postmenopausal who do not have Chel atrophy (rated 2 Yo by ic gana women

those after menopause).

The residual amount 7975 for postmenopausal women with estrogen atrophy is not associated with vaginal secretion of compounds” (Wines and Willsteed 2001; N.A.M.S. 2007).

In the systemic circulation due to ay cessation of systemic secretion of estrogen secretion in JS 0 - women at the time of menstruation. Subsequently; Deficiency in the secretion of lawn g estrogen is not correct for the occurrence

Symptoms of vaginal atrophy in most women after menstruation.

Nevertheless; Sex steroid formation does not stop with cessation of ovarian function

ovarian function in the postmenstrual period. Progress (Jal) illustrates our understanding of the physiology of the glands

sa endocrine physiology Women know that after menopause; Jia DHEA Vo secretion by adrenergic compounds The only source of sexual steroids that has been exclusively

Their composition in target tissues (Labrie 1991) target tissues

Unlike estrogen compounds of ovarian origin, which are then secreted in the vagina

general circulation as it can be measured” and DHEA represents a non-productive substance

Active, which were transformed in peripheral tissues at multiple rates according to the level of 0 expression of steroidogenic enzymes in each tissue. allow the excretion process

The intracrinology process is involved in the formation of the localized internal tissues of the sex steroids

Active with a distinct release of active steroids into the circulation.

Labrie, Dupont et al. 1985; Labrie, Belanger et al. 1988; Labrie 1991;

Labrie, Luu-The et al. 2005.

oYAY

And

However, DHEA secretion decreases with age; a decrease was observed in 70680 at

cycle time

2005; Labrie, Luu--. 2003; Labrie, Belanger et al. Labrie, Luu-The et al

. 2006; Labrie, Luu-The et al. 2005; Labrie, Belanger et al..The et al

2006; Labrie 2007 ©

The only difference is between women who experience postmenopausal symptoms and those who don't

Its symptoms are in the amount of DHEA secreted by adrenaline, or tissue sensitivity

Sensitivity of vaginal tissue to DHEA is likely to be related to the difference

In the sensitivity of women to an unknown extent »; And the activity level of the enzymatic machinery 0 specified for each cell type Labrie 1991; Labrie, Belanger).

(et al. 2005) With this knowledge, DHEA is a hormone replacement therapy

Physiology for postmenopausal women.

As shown in previous studies:

2005: . 2003; Labrie, Luu-The et al. Labrie 1991; Labrie, Luu-The et al 2007. Labrie, Belanger et al \o

Supplementation with physiological amounts of exogenous DHEA allows biosynthesis.

of androgen and/or estrogen compounds only in suitable target tissues including

Steroid enzymesogenic enzymes in the case of internal secretions intracrinology

Jas.) 2005. Labrie, Luu-The et al.. Active androgens and estrogens locally synthesized by DHEA in peripheral target tissues.

Its effect is in the same cells where it is formed. usefully There is very little leakage of steroids

active sex steroids in the circulatory system is thus interpreted

Significant benefits observed in the vagina with no significant change in yestrogen androgen cycling

docal biosynthesis drives this local biosynthesis (Labrie, Cusan et al. 2008)

oYAY

A

In target cells by removing exposure to an increase in androgen and estrogen and the effect and inactivation of sex steroids, and thus removes the excess risk of unwanted side effects; ovarian and ovarian cancer, including estrogen, from exposure to excess levels of the uterus: (Gambrell, Massey et al. 1980; Persson, Adami et al. 1989; Steinberg, ©

Thacker et al. 1991; Voigt, Weiss et al. 1991; Sillero—Arenas, Delgado—

Rodriguez et al. 1992; Colditz, Egn et al. 1993; Jick, Walker et al. 1993;

Colditz, Hankinson et al. 1995; Grady, Gebretsadik et al. 1995;

Collaborative Group on Hormonal Factors in Breast Cancer 1997; Garg,

Kerlikowske et al. 1998; Coughlin, Giustozzi et al. 2000; Halley 2002; 0

Lacey, Mink et al. 2002; Riman, Dickman et al. 2002; Rodriguez, Patel et al. 2002; Rossouw, Anderson et al. 2002; Beral 2003; chlebowski,

Hendrix et al. 2003; Holmberg and Anderson 2004; Beral, Bull et al. 2005; Lyytinen, Pukkala et al. 2006; Corrao, Zambon et al. 2008;

Holmberg, Iversen et al. 2008; Li, Plummer et al. 2008). 0 is an integer variable that reflects the beneficial effect of treating vaginal atrophy. PH represents the change in pH

E2 a week of intravaginal treatment with 75 micrograms of VY after 771 compared to 751 had a pH of 5.00 less than the percentage of patients who had a pH (Bachmann, Lobo et al. al. 2008) placebo group had a lower pH and 7917 women had a pH of 7 11.7 though at the baseline”; 0 (eg ERC-210 clinical trial) had 0.5 of JB at the start of treatment and 0.5 of JB had PH No. (7) ); No patient had a WEEK pH in the VY group less than 0.0 at the onset of the PH, pH TEA LET AY, respectively. DHEA zero#; And 760.5, 70.5, and 7291.0 are from the BD groups

In the Jil) ERC-210 clinical trial (No. Y), the effect of DHEA on the maturation of vaginal epithelial cells was particularly rapid: 70.5 DHEA ovules were actually observed. And 75% of the maximum WAY effect on parabasal cells adjacent to the base at 2 weeks, while 747% of the maximum stimulatory effect was observed on the superficial cells at the same time as the interstitial sal. Ao 7 verified the maximum effect of 0 + DHEA on the percentage of surface cell turnover in a period of 6 weeks Judy 777 of the maximum effect of 70.5 DHEA on the most fatigued symptoms were observed in a period of 2 weeks and reached In addition, only 17.8 7 women showed no change in their most distressing symptoms in the 7 week VY period in the 0.5 7 DHEA group compared to EAA. In the placebo group, the effect of DHEA on the parabasal cells was rapid, since the parabasal cells decreased to less than 7 01 in one month of using three doses of DHEA. The effect was seen very quickly with 7001 of the observed effect per week ¥ at a high dose of DHEA (71). 1 In a study of vaginal estrogen cream or tablets; Approximately 750 effects measured per week VY were observed at 2 weeks (Rioux, Devlin et al. 2000) and this data indicates a rapid effect of DHEA not insignificant and possibly outweighing the effect of vaginal 2 and estrogenic formulations. conjugate. In a study of the effect of oral estrogens in postmenopausal VY women, daily administration of 7 mg of conjugated synthetic estrogens resulted in a decrease of 0% parabasal cells from 777 to 77.7, whereas daily administration of 7 mg of conjugated synthetic estrogens The surface cells led to an increase of Y,\7 to (Marx, Schade et al. 2004) 7 15,4 in a study comparing 67 mg and 15 mg doses of conjugated equine estrogens (Utian, Shoupe et al. 1) The 15 mg dose showed a greater effect on the percentage of WAL Lad superficial cells OV AY

Meh in the current study; The vaginal maturation value (VMV) increased from YV, 0 at baseline, to 51.85 eee (<P) in ic gana treated with estrogen (Simon, Reape et al. al. 2007) the percentage of superficial cells increased by 17.15 from the baseline, while the percentage of parabasal cells decreased by 1.17;7 in the group treated with ©65100960. In the same study, the vaginal pH decreased Vaginal pH from 74 at baseline to 5.05 (a decrease of 1.159 or 774) in the estrogen group (most symptomatic Bla) decreased from 7.54 to 0.64 (- 1,54) in the estrogen group compared to the decrease from 4 to (1.84 0) placebo (V0). This data observed with the use of estrogen can be compared to the 1,576 decrease in the severity of the most debilitating symptom at 11 weeks. in the DHEA 7 v0 group and a decrease of 0.17 in the placebo group observed in the clinical trial (Example No. 1). ERC=210 at week OY for 7911 ESTring cases was And 7274 of the Vagifem cases had persistent atrophy of the epithelial cells.At week fA, the corresponding values were 748 Ves (Weisber). g, Ayton et al. 2005) week ¢A of treatment with Vagifem and 517109 0 777 women still had vaginal dryness (Weisberg, Ayton etal 2005). On the other hand, vulvar itching persisted in 795 and 7270 women. after treatment with ESTring and Vagifem respectively while 7 AYA still had dyspareunia after treatment with VAGIFEM 5 ESTring respectively Bleeding after LY progestogen test was in sal 7 group jiay Vagifem group .ESTring Yo after three months of daily administration of 1Y0 + mg of Premarin by mouth or in Jagd (in the form of cream) an improvement was observed, respectively, VT and 7975 in dyspareunia (Liu ©] al. 2006, 1009). In this study, it was found that 1 gram of VAY in Jie Premarin cream was the lowest dose for the treatment of sexual dysfunction in women who received 2 micrograms of Yoo transvaginally; Jue sexual intercourse was present in Yo 277.4 of the cases after VY month of treatment: oY AY

— \g (Simunic, Banovic et al. 2003) The success rate of topical treatment of E2 tablets was 854.5 7 as indicated by patients and aA , 1 7 as indicated by dail gs a by doctors p: (Simunic, Banovic et al. 2003) and Bachman et al. 1947: (Bachmann, Notelovitz et al. 1992) showed that from 500 to 7,500 women showed Oral estrogen replacement Complaints of vaginal dryness. As shown before, after VY 1 hour of treatment with Labrie, Diamond et al. ( DHEA 7 ) Clinical trial ERC-210 (Example #3)) showed no effects on endometrial tissue yet? months of administration of the DHEA product via Jud) as indicated by histological examination of endometrial biopsies obtained before and 0 11 weeks after treatment. These data are consistent with le aromatase activity in endometrium Baxendale, Reed et al. 1981; Bulun, Lin ) human endometrium ga. (et al. 2005) These data are strongly corroborated by the well-known clinical observation that endometrial atrophy is characteristic of postmenopausal despite persistent secretion of DHEA. Throughout life: (Labrie, Luu-The et al. 2005; Labrie, Belanger et al. 2006) 0 The absence of the human endometrium of the steroidogenic enzymes necessary for the conversion of DHEA to estrogen compounds is consistent with the role Physiological endometriosis that is exclusively active during the reproductive years when its function is primarily controlled by ovarian hormones and placental origins for 018066018. There is no physiological role for endometrial YS after menopause that would demonstrate any effect Continuous production of estrogen compounds after the cessation of estrogen secretion through the ovary, therefore, the enzymes required for the synthesis of estrogen compounds from DHEA are not expressed in the endometrium, which is a tissue completely dependent on estrogen compounds of ovarian origin. ovarian origin oY AY

A: Estrogen compounds alone were shown to stimulate endometrial endometrial cells (Smith, Prentice et al. 1975) proliferation, while progestogen compounds given in combination with estrogen compounds inhibited the stimulatory effect of estrogen compounds. estrogen (Feeley and Wells 2001). Because androgen receptors are expressed in human endometrium and stroma cells (Mertens, Heineman et al. 1996), it is important to mention The clinical study that investigated the effect of J androgen compounds shows the effect on the endometrium of a relatively high dose of sal testosterone in postmenopausal women (testosterone undecanoate) 560 mg every second day) (Sahlin et al., 2809, 2007). . In women who received estradiol valerate

0 (7 mg/(Les) ionization constant numbering increased by 7 500 at ? months of treatment while immediate administration of testosterone decreased reproduction to 7748. The numbering increased by 6167 only in the two groups that received 6510981 However, it was decreased by addition of testosterone in the stroma cells. While testosterone did not have a stimulating effect on endometrial proliferation in women, it was shown to produce an antiestrogenic effect in the endometrium.

0 While FDA guidance urges funders to establish minimum doses and exposures to both estrogens and 009651096 compounds, it should be recognized that although 7000 compounds are effective for correcting symptoms of vaginal atrophy and vasodilator symptoms; Nor Ji 800309860 compounds physiological hormones that allow © 77 postmenopausal women to avoid symptoms that range from moderate to serious for

Yo for vaginal atrophy. These women remain relatively symptom free throughout the postmenopausal years. Since the only source of sexual steroids in women after menopause; In both asymptomatic and asymptomatic women” 5105/0155 biosynthesis of L-6510960 and androgenization of cadrenal DHEA by endogenous secretion mechanism. Replacement with DHEA represents only the physiological method that allows supply to women who

Yo suffer from postmenopausal symptoms with the missing amount of DHEA responsible for these

oYAY

Speed up your symptoms. DIY method Hormone precursor replacement therapy (HPRT) should correct vaginal atrophy and symptoms of vasospasm change with no greater risk than postmenopausal women who do not have symptoms of vaginal atrophy due to exposure The highest levels of DHEA and sex steroids that are produced in cells endogenously by the process of endogenous secretion ntracrinology. It is preferable that the sex steroids produced according to the invention be administered in a dose range of (1) between (1) to 100 mg daily; (preferably from © 0 to 5 mg daily; preferably ∼ to 0 mg daily); when administered vaginally Jah; (7) in a dosage range of 15 to 100 mg daily ( Preferably Th to 100 mg daily); when administered to the skin; (TF) in the 0 dose range of 0 to 100 mg daily (preferably YO mg to 100 mg daily); Vo Sie mg daily; when administered orally; or (;) in a dose range of 10 to YO mg daily (preferably TOYO to 10 mg daily); That's when he is given a non-m gob Howling (i.e., in the “muscle” or “subcutaneous”). In a pharmaceutical formulation for vaginal administration; It is preferable that DHEA or any other sale Vo product be present in a concentration between 0.1 and 1071 by weight in relation to the total weight of the composition and preferably between 0.7 ZF, by weight and particularly between 175 and 1 ,27. For example, 0.7 milliliters (de) of vaginal suppositories containing 70.5 DHEA (by weight of the total formulation) were administered; And that once a day; It is preferable to provide 1.0 mg/Lag of Sa DHEA using larger or smaller suppositories as different concentrations; while the dose is kept within the required range. 0 in a pharmaceutical formulation for percutaneous administration; DHEA or other substances produced in a concentration between 0.1 and 0107 by weight in relation to the total weight of the formulation and preferably between 0.7 and 77.0 especially between ANTI ON AY

— g in a pharmaceutical formulation for oral administration Oral Preferably DHEA or other produced sale at a concentration between © and 7958 by weight in relation to the total weight of the formulation and preferably between 01 and 0 aly Jo between ‎ Vo and 12 vA in a pharmaceutical formulation for non-intestinal parental administration (i.e. through the cintramuscular muscle or subcutaneous), it is preferable that DHEA or the other produced substance be present in a concentration between 1.7 mg/mL is 5 YO mg/mL; and between Yo ERE 10 mg/ald 3 Je is better than Y mg/Je and Yo mg/Je. JE on the efficiency of the invention: Example No. (1) 0 Clinical Trial 40-213 Bioavailability of DHEA after administration of vaginal suppositories in postmenopausal women with first-stage vaginal atrophy; in a randomized controlled study pharmacokinetics and topical effect of daily administration of DHEA suppositories for a period of 1 week. The primary objective of this study was to evaluate the systemic bioavailability of DHEA and its metabolites 70 Uae after daily administration of DHEA suppositories into the vagina in Arb. different concentrations of DHEA. This study was a randomized, placebo-controlled, placebo-controlled trial with 01 subjects per group. 56 postmenopausal women were thus randomly assigned to receive a daily dose of one suppository of the following concentrations: 70.6 0.8 7 (1.0 mg [DHEA 0 suppository]); or 7 mg VY [DHEA suppositories] or VA (7.4 mg [DHEA suppositories]. Bad

The maturation index, as well as the vaginal pH, were measured at the pre-treatment stage as well as after 17 days of treatment to obtain an explanation of the topical effect of DHEA during the 35-day short treatment. As shown in Figure 1b; Table 1 and Table 7 daily intravaginal administration of 0 to VF ml of a suppository containing 670.5 721.0 and 21.8 of DHEA resulted in Continuous increase of DHEA in serum with an AUC value from zero to YE hr reaching 74.8 + 54.8 ng/hr/mL; 8.7 + 8.9 ng/hr/mL. (>P) #2 ..) 07la + 011 ng/hr/ml (©< 0.00 MEY) + 4.597 [aha] [aha/ml (©<) (v0) on Thus, there were increases of NYY, 7707, and 1771 compared to the control sample when 0 doses were given, 250.5, and 21.0 and 21.8 of DHEA, respectively. As observed for all other steroids; Note similar values for AUC from zero to YE hours per day 1 and 7. In fact, similar to the mean serum value of 54,776 + 0.47 n[aha ml of DHEA after Treatment with the highest value (Table 7)) with a value of 4,497 + YA ng/mL in (BY) normal women aged from Vo to Yo 358 years before menopause (Labrie, et al. 2006 0:©861809. The survival of serum D is well illustrated in Figure (IV). HEA after any of the doses of DHEA used in the limits that women have before menopause. As previously observed following oral or percutaneous administration of DHEA (Labrie, Belanger et al. 2007) serum 5-Diol concentration follows a pattern that is not possible for DHEA although lower concentrations may be observed.In fact, the AUC ranges from 0 to YE hr from doses of 8.10 + 10 ng/hr/mL in the placebo group per day. 1 to AY + YV, AY + 1, or ye 0 > P) (v0) >P) 0.13 + YY 0 , 5 (0,0) >P) at 78 and 21, 0 5 DHEA YA respectively (DY) Table 1. These changes correspond to increases in TEV VEY 5 Vo over the control sample. Only 71.8 per dose of DHEA causes increases in serum 5-Diol concentration that oY AY

-01- Exceed the values present in normal premenstrual women (Fig. No. (QV) during YE 1 hour after vaginal administration of DHEA on day 1. The AUC value ranged from zero to; 7 hours of Testo serum No changes at dose 70.5 (79, + Fe ng/hour/ml vs. 7.58 + YY nano [dha hr/© .ml) in the group that Receiving restorative therapy (Fig. L(Y) at doses of 20.0 μF), A values of AUC were present from zero to YE hours of 5.54 + (4.8 nM) aha h/mL £0.8Y 5 ).,.# >P) 14,” ng/mL (©< (0+) in Table 1))These values are translated into an average Serum Testo levels of 11 T + d EATS (SIN) milk (SUN) 0045 + k (0 tH 4,00) and Ka + A (©< (4,0) nano de faba on Even in the highest dose Ala use (771.8 DHEA) serum Testo levels remained within the normal range for premenopausal women at 18 + 0.07 ng/mL (00 - 071 from © 2006 to #30 (Labrie, Belanger et al. (Fig. 1e). From dex gal, the dose corresponds to 71.0 VA + 07 ng/( Je The values that exist for women before menopause; Specifically, 0.19 + 1.4 (Fig. 1e). ve in Fig. (oF and ed); Lad (DHT) increased the AUC value from zero to YE h from 4 + 07 ng/h/ml in the satisfaction drug group on day 1 to 6.97 + (SIN) 1 and 17 +1E (P) YY £1,475 (4,00 <P) (0,+) n[aha h/mL in 750.5 21.0 ZY A5, 21.0 (DHEA) groups, respectively (Table L(Y) these values correspond to mean serum DHT levels of 7 + cn (kong an) 00 v0) + 0A e 1 0 nfaba mL (Table oY is thus Reaching the highest dose of DHEA and normal serum DHT levels of 0.07 + 0.07 ng/ml were observed in premenopausal women (2006 (Labrie, Belanger et al.) (Fig. 1). f) Mean serum [AE] concentrations were measured at 0.41 + 17.6 ng/mL in the group taking homeostasis on day 17 (Table 7)) while it was not There is a significant change in Yo at dose 76.5 0.04 + 15.4 (DHEA ng/mL).An increase to 7.1 + OV AY is noted.

7g 7.4 ng/mL (Y,A0 + Yo, 6 oo) ng (P < 1 ng) Je 0 at ie (DHEA 71.5, respectively). AUC from zero to YE hour in Figure No. (b) and shown in Table No. (1). Average concentrations of 2 in serum were measured at YY + pico faba mL ets. + 15 pico©g/mL (SN) in the satisfying drug and 5 and 7 (DHEA) groups, respectively (Table 7). The mean concentrations of 2 L were 6.01 + 0.71 Su. (g/mL (P < *#...) AEE 0A pg/mL (P < 05),) per day 1 in women receiving doses of 71300 and 8.17 DHEA as a result of absolute increases 3,18 5 7.85 pg/mL compared to placebo, respectively.Data compared to 1-5 serum concentrations were observed with mean 0 levels in serum VY + 0.7 ng/mL and 0.31 ng/mL. faba sl mL (SN) groups receiving HRT 5 74.0 of (DHEA) respectively (Table 7). 0.07 + 0 VA ad ng/mL and faba sli, Yo £0 Yo ml in the 70300 groups (DHEA 7 VA respectively. Only the 71.8 DHEA group showed a statistical difference <P) (0+) compared to the group that received placebo. Vo as shown in Figure (b); friendship); A comparative pattern is observed for 1-5 DHEA-S. The AUC value from zero to Yi was measured for a concentration of 5-0115 in serum at 8.75 + 7.77 ng/h/mL in the control group. HRT received 11.7 placebo + 7 tano [aha h/ml] in the group receiving 0 + 7 DHEA (for 5.1). With Jef given two doses of DHEA, AUC values from zero to YE were measured at 16.5 + 7.71 nYg/h/mL (SIN) and 14.7 + 2.529 ng/hr/ml(©<(v0) respectively (Fig. caf. Table 1).(All 01458 values remain for all Ji DHEA wounds from Lad) DHEA-S levels. observed in premenopausal women (ally) showing an average TY + 1.77 tg/ml (Y) c). As shown in Figure (b); The AUC value was measured from zero to YE hr from -4 Yo 01006 serum after administration of DHEA on day 17 at 1.74 + fire 5 ANY + each OV AY

—oA- for the HRT group and the group with (NLS) g/hr/ml sl higher; DHEA increased by 7.5%, respectively. When administering DEAH doses received 70.5 from (P) > 1.51 + 11.1 hours from ; - Dione slightly to YE) from zero AUC values ng/hr/ml, respectively. As can be seen in Figure (7d) and Table No. © Observed in normal women prior to menopause (Lad 4-dione) average concentrations of +0,5 + Lad 4-dione were higher than the average DHEA concentrations of the cycle. In reality; A dose of nanograms/ml resulted in an average value of 0.97 ml for menstruating women (Labrie, Belanger et al. 2006) [ala $l +, Yo + 0.97]. Ll Yo to 0 of the serum dione levels observed in 7#50 thus only reaches oY (Appendix 0 in premenopausal women. -07 for 8001-6 and serum levels When taking into consideration the critical role of serum levels (20), it is preferable in (Labrie, Belanger et al. 2006) diol -07 and “GY - diol mL faba nano 0.01 + 6.99 to observe an increase of 0001-6 from the mean value of (V) and table number of g/hr/mL in the SLY group, + 14.7 in the group receiving BRT to V0 ng /hr/ YAN + values of 14.7 + 1.58 nor,8?., DHEA 8 <P., 10 were measured vs. the group that received P>00, respectively (DHEA 71, 89 79.0 mL in groups DHEA for both groups treated with placebo therapy satisfactory - diol — and 38 17G - diol — androgen 38 Similar changes could be observed for small metabolites from Table 3 (7).It is important to be clarified; as (1) (1Ab”; Perform the spelling of Table 176 vo the highest used; DHEA remained that even in the case of doses (A) shown in Figure No. - diol and 38- 36 - diol - 6 38 - ADT for serum levels average serum levels present in serum levels And 71 are below average serum levels 11 and 6,291 women before menopause.

-and 4e-

As shown in Table No. (7); The amount of glucuronides metabolites produced

measured at a period of YE 1 hour per day to give 7 Jo), from a suppository containing DHEA 71.8

YY) mg (DHEA) is YAY ng/mL while the mean serum concentration of the same

Metabolism output in women who had menopause before 35 and their age ranged from Yo

© 2006 (Labrie, Belangeret al.) (Appendix)

L(Y) thus lel leads to a dose of DHEA used to be only 765.7 of the value corresponding to the DHEA metabolites.

Kidney metabolism in normal young women who have their period.

On the other hand, doses 70.5 5 71.0 of DHEA lead to amounts of YAY metabolites.

ng and 71.57 ng/mL, respectively; Thus, only 0.749 and 750.7 of the observed gal values correspond to premenopausal women (Fig. 5). We've already reached out

indicates that daily oral administration of 100 mg of DHEA leads to VE 7 levels.

present in women before menopause (2007). (Labrie, Belanger et al.

We have noticed before that after DHEA is administered through the mouth or through the skin, changes to DHEA occur

praying about 7000 is an overestimation of changes in composition 5163010 which is reflected by 0 changes in 1-6 nl, 38 - diol - 36 and 38 - Labrie, Belangeret ) 176 - diol

(al. 2007).

As shown in Figure (9); The mean serum DHEA levels moved from 777

For the value observed in premenopausal women in the treatment group

placebo to ZVY 5 oY and 6107 in women receiving doses of DHEA 0 at concentrations ZY, sho and 21.8, respectively. The data of Figure (9) indicate that the changes in

serum DHEA after administration of DHEA in died) is also an over-evaluation of changes in

Configuring androgen and possibly also configuring estrogen as shown by

Smaller changes in serum 5-51 (Table No. 1).

Ada

=« a — actually; At dose 0.0, serum androgen_ladl_045 metabolites increased by 770.1 from the value found in premenopausal women, while serum DHEA increased by 749.1 (700 percent overestimate). . At the highest dose (DHEA increased serum metabolites by 747.1, while serum DHEA increased (ZY (AY, 0 2 o) overestimated). Table No. (1): Areas under the curve (AUC) from zero to 74 hours) for DHEA and eleven metabolites on days 1 and 7 for daily administration of DHEA suppositories in the vagina to women after their period Menopausal women range in age from 0© to VO years and have vaginal atrophy. Yes E2 El DHT TEST DHEA 0 value asf asad] asa] "yo yo yo 1 asl day 'day 1 day V day asl] 1 the 1 vay dvd 11 leco pico apico l" nano collection CL . nano sit gr/ gr/ gr/ Sa 3 nano il g/g | ba gram/ field field gram/ sd | ol "| sa asa fic] 1 qT amenity/remediation 5.5 Y |

9 1 ay Al Jah +, Al al or 0 of AY 7 Lh 1.08 "7.117 Mar al-Ara title abt 75 F SE 7 1 YY Yel 0 q 7 M

ALA AVLY YI] YY AY AY YY Insomnia Yel oT 6.1 Meto DHE

Y 9 13 oY 5 \ Ya] AY] 11 VV 9 Lb A

VA 0 , © ATA YY,Y EAA 4 ol When Aral Ab ARYA SE 1 2 1 1 Yeo Ya] 04 Y 2 M

YEE, Yo | OVAL EYAN,YY YY

Ye ov 09 A og va] Al Ak YY Y Lb A Kk La 3 M Rah Etc Al Aam v4 Altama Dal ye LY SE L L 0 1 1 Ve] YY, 11 Y.M

AY

YY AY] Tea | Lt 1 For God this is for God off of YY YAY YEYYY,| ak DHE

YA 1 ay Ve av VY «| AA 0 oY Lb A

YY] in 2 ZY, A

YoY] YY, TAY] I Vy, «| 4,414,¢v| SE 7 5 5 A Umm Al Latkla Lak M 11 diol N- ¥| diol n- ¥| ADT-G| 4-dione DHEA-S E1-S 176-| 3G - Refund group

-?1- today all asl) asl) asl asl asl] today asl |

Wad Re SY SY Ananu Anu Se Se sl si no no no crime/ hour/ [ea [ea] crime/ gram/ of gram/ crime/ crime/ [eb gram/ | An hour in grams / hour / | hour hour hour hour hour/hour ac La ml |[ ml h ml ml |/ ml / ml / ml since || ML EYES ML 117 YY, 0 vy fay [ava] uy LY] ALL AY] YA] 1 Treatment 0 7 0 00 , Ya , oF 4 7 1 7 5 177 Satisfying Yo “ov yee 0, YA, Ye, lap b Y, ¢ a p 1 a mother’s flesh 11 a 1

UY YE] yy vey Av Av á l l ád vo DHEA $ A either um AE ER EE 0 or oa ¢| a m 2,7 0 y, av Y,e q0, YY a a 95 ladan 4 b a vy] aa] | A ML 0

Ye, Yo, Al Let's go to hell aay ay apple vel ve | gv vo DHEA $A s| yvy| ol vy | Ya a ¢y| except ¢ AE gs. vol nal wv vol “RA YN A ON] EE ER ER | ¢¢ YY, Ye Ye lave son ye fv] ve | oa] Tech DHEA

Y 0 a l h l vy 41 h vl aa vl ov ZY, A s vol I cry for you a love ox] Al l veal l ell ey ydl

A3: Data for one patient were excluded. Table 7: DHEA 1Average Serum Steroid Levels and eleven metabolites on day 1 and 7 of daily administration of vaginal DHEA suppositories to postmenopausal women ranges between Their ages ranged from 00 to 10 years. Vo mals had atrophy in the vagina. The values were obtained by dividing the AUC values from zero to YE by the hour measured on day 1 and not by YE, thus leading to Average serum asteroid concentration per YE hour period. Serum steroid concentrations in women aged 30+ were added to lle vo in lesa before Uads) & cycle for reference 11 yo yo asl] asl asl] asd asd] asd] asd asd] asd asad] ER RA ld y ld ld ld | The total value of the LED is Nano, Nano, Micro, Early and Nano, Nano, Nano, Nano; no ah amicro amicro ET IE I Ih HE He IY gram for gram g/g/g/g/g g/g/g/g/g/h IPS PTW PS RPS ER I PSV | 2 ac ly h acl lel 2 WY mL Je 3 mL 2 / mL A EYRE EEE RY EY EY A JE J IEE Teach Na Na A A I Art Fact OV AY

please [YY] SEM| mt a ra ra a a a ge 8 71 Yo, YE, vor] +1 1 Ya] YA Y gl 1 A no ¢ v,20 I SEM M AY 14 + © , 9 % ve ve ve 0”, 0”, lat Y v8 Es 1 7 Y 0 oY «0A «04, VY L.gad DHE bh oye] lm [8 EY] YE, VV, Lami eo] £7 9 AY A No 11 RY.

EIA SEM to 4.41 | Ra 9600 oY p ve ve ve , A A 0 ¢ YI A A 2 DHE averaging AB AB A cap OTA Y, VEL YO, YA, “| oo oo oY] +, YY] “AA Al eo A © A except 03 E SEM x LAE 29 EAI 961 0”, p Y y, ov ve ve Y q 7 a yo 11 before regression period Ye +, 29 1 AY lym 711 0 AY, Uads) & CY xe 4 rad YY,YAl the standard course Amard 07 28 YY , YA 1 AY AY YY © to AID bs 0 bs a # 0 a # 0 bs 0 * bs n) 71 YY, YY,Vi oY 0 Yo 1.07 gq] to 64 to +7( voq,av[ £1 AY NY (Yo | to, + — ovo) yen) - as AAA ERA ai, out SV AY

M?- Bin Qeema - 0(041) LV( 078( AIR 0) 1 Group ADT-G| 4-dione| DHEA-S E1-S |¥ n- ¥|diol n - diol that -36 |-176 treatment placeb 0 day 1 |day ast] as] ssl] as ms] atoday today ast as as] nano 7 1 7 1 7 1 7 1 7 1 7 Value g/nano MEE EEL BE RE EL I BPE IPS lo lo lo hour/ gr/|f , fobs gr/ gr/ agam/ fea] button for me, g/ g/[eb] J hal de La J hour hour hour hour de ly ol laalice hour del ml hour ml |/ ml |/ ml / ml fl ml / ml |/ ml 0”, 0”, 0, 0, 1 0 77 1,4 0« |0 1 Y 7 1 1 1 fo] fo] Y ve Ag vr vr \,Y \, Y vr vr 1 vr 1 Y 0 q Y q 0 Y Avg. 11 Le for Saab ER ET ER of B= A RFI ER 1 Yo 1 A fo] 7 7 DHEA 1 7 0 17 SEM |©, + / for YY ve ve A 2,7 ve ve 1 1 ve L OV AY

-1?-

Yoo AL GAL Father YA, YY [Akeh A TT] Bite as sid DHEA ¢ La ¢ 11 edh €) 1 9 0 A 960 171 SEM 0”, 1 1 1 Y Fa 0 0, 1 1 ve 0 2 2 o AJ 1 1 1 Y Y

LYE 8 Yo A Yo, YY, F og] AL TY] YA Lassi DHEA ¢ A A of Ve YA 0 ¢ 1 ¥ 2 961 11 SEM 1 1 1 1 Y,A 7p 0, 0, 1 1 ve

A 1 4 0 IN 0 "9 "9 1 1 fo) A 01 671 +41 aaa 1019| Women Standard to "EU 4" 8 A Lar] A to TT cut off 965 H 1 AAR +, ay A LAY + Adam cycle 8. - oxo = x avy - ge] = e -. © ) and the following (3) - meter) duff tra ed to d l vou | Their age is -,75( — YY) (YI value range) =, Yo) —0,A7) =, VY) (£,7F (V, vv Yo) from (0, (FY) , (m (Vo to =n) 7 (Labrie, Belanger et al. 2006) One patient's data is excluded. 8a

— 7a — However, as shown in Table 7, it should be mentioned that there is a tendency to have low pretreatment ad for many steroids in the placebo group. Especially with low values in the group receiving placebo placebo for (DHEA © Dahmattana 4-1008 (E2) DHT (Testo 1-6 Nlf Roh30- .17G - diol) given that all average serum steroid values that observed after administration of DHEA doses of 70.5 and 71.0 to remain within or below the values found in normal premenopausal women, there is no attempt to correct for this apparent deviation. In YE hours per 0 steroids measured on day 17 of daily administration of suppositories DHEA at a concentration of 70.5 closely correspond to the values measured in women aged 00 to 15. years, while DHEA suppositories at a concentration of 7001 lead to ad within the range observed for normal women aged 5 to 10 © Labrie, Belanger et al. (lle 20) 06(- 1) Given that oY metabolites represent the most reliable measure of the conversion of exogenous DHEA Las into candrogenic compounds, current data indicate that even at Jef Ala doses of DHEA used in The current study fulfills FDA requirements for serum levels that remain within normal (sad) in normal premenopausal women. Table (1): Data for basal Lad steroid levels on day 1 nor 0 of daily administration of incremental doses of DHEA vaginally are expressed in nanograms/ml except for E25 El (in picos) [aba ml) 5 DHEA=S (micro faba ml).steroid therapy DHEA 3.1.DHEA|Z.,o DHEA seductive gratifying oY AY

Yo + 4414 YA + 4 + Ka VE + Today Dog DHEA

Yes 1

YY VAY A + Ha + 3,74] «,Y¢ + +719 Day 7 5-Diol Day Cb + To Aa + 1 + In Da + To 0 0 0 Ag 1 today vet + 1 eo + 1 + FY, + 1 7 for ‎sey] sow] reassure x.ovvr| Alerum DHEA-S

LI 9 p v, 1 0 1 5 7 vv, 1 0 Y 1 + Fala + Qadi + 7 + “YA today ARAN AR SY Yeo 7 SO = I Oh ef + YY + YY, Y VA count today 4-dione 0 0 0 Ag 1

NO + go to + of 4 + to if £ + V1 today 0 0 0 Ag 7 Testo today oe, eee + 0 + a = NA d + ka 0 0 0 1 1 today ER I SO Be CR on + eV 1 NES 0 0 0 1 7 Reply to

-1?- A L L A + ve AY + AY + Vo + 0 YY Today Lamai NA 4 A 7 Lamakha 1 Kara Lakv + 11 + YY,AY + YY 4A today El Dara 1 Ma + 1 Alalar 1 + 1,0 + \Y,oV + 1/11 Today 211 AA 7

GAY + Solution Ara A 0 + Today + Laa Aa 1 A 001 + Tee 1.1 + 0,4A + Sac “, YA£ Today Dara +0 7 + 64 + .,11 Lala + AI BE ETA AR today E1-S oe YY 0 NT +, + Y4 A 4 1 + 104 + YY + ,V0) + VEY] today 17 4 ve ru 0 in" except 7 ra ‎ + 94,82] 01 + 48 + 0 Day 7 Ra Ava ADT-G

Y,V) 1 ra for your son 1 + love 1 + 14 + today aba + akhlaba nba ok 7 accept + in yee today) + + ala - diol - 0 and 1 36

1 “= od +,Vo + T + Yo + T + Yo for 1 diol -0 - dd “AL + AT + YY AA AT 1 1765 day a + y 2 y y y yyyyyyyyyyy ER 7 8: steroid levels were below the limiting limit for all subjects (quanting limit - 1.0 ng/mL). After only a week of daily administration of DHEA suppositories, the maturation index increased (P) 1 (ov) 2 maturation index 6, (>P) by 6, and ALN (>P) (0 º) in 0 #, E +2, 0, 7Y, A 5 ZV for the groups that received (DHEA) respectively (Fig. No. (1M 1) (no changes were observed in the group that receives satisfaction treatment between days Vs) and on the other hand a decrease Vaginal pH from 1.75 + 17, to dar + at 1 + 1.8V «(v,10>P) to (ve 1>P) YY + o,¥1 and from 7.0V + V to <P (YA + 7 00 +) respectively in the groups receiving DHEA at a concentration of 6.5 7 As J , Yo 7 (Fig. 0 1b) There were no changes in the vaginal pH of the group receiving the satisfactory treatment.Example No. (): Bioavailability and metabolism of Dehydroepiandrosterone and its transdermal administration in postmenopausal women.-1 Yo Introduction SY AY ‏

Ally (DHEA-S, especially DHEA) secretes large amounts of inactive steroids from peripheral tissues or 101 effective in peripheral tissues [transformed into sandrogens] (Labrie, 1991; Labrie, Belanger et al., 1995; Labrie, Luu-The etal., 1997;

Labrie, Simard et al., 1996; Labrie, Luu-The et al., 2005; Labrie, Poulin 10 et al., 2006 and Simpson 2000). in 38 adult men and women with a higher DHEA=S number in fact; Levels of 0001 and higher are many times higher than testosterone compared to levels of 5000 to 1001 times higher, thus leading to a large store of the basic substance cestradiol to 10,000 peripheral levels and or 5 in peripheral secretory tissues androgens convert to 0 to DHEA which involve the enzymatic mechanisms necessary for the conversion of intracrine tissues

Labrie 1991, and Labrie, Luu-The ) active sex steroids

VAAA actually; The term exocrine science was first coined in (et all, 2005) active steroids prepared in the same cells to describe the synthesis (Labrie, Belanger ©] al., 1988) of extracellular space, showing their effect with no release into the extracellular space 5 or the presence of little release before it becomes non-general circulation and great circulation (Labrie, 1991) activated by adrenaline during advancing age DEHA-S leads to a significant decrease in the formation of

Belangeretal., 1994; Vermeulen and Verdonck, 1976; and Migeon et al. (al, 1957 | 0) in peripheral tissues leads to a significant decrease in the formation of peripheral target tissues (Schriock et al. 1988 and insulin). Insulin resistance Jia with age (Nestler et al. 1988; MacEwen and obesity (Coleman et al. 1982) which is given to postmenopausal women with more attention,” especially those related to bones; DHEA Yo oY AY

insulin 00618501157, vagina 789178, glucose ©911005; Insulin metabolism cskin and skin : oral administration which is after oral administration fat mass and fatty masses

Villareal and Holloszy, 2004; Baulieu et al., 2000; Morales, et al. 1994; and Kawano et al. 2003. This becomes of particular interest (Diamond et al., 1996 and Labrie Diamond et al. 1997) to gain more specific knowledge about bioavailability, pharmacokinetics and metabolism. DHEA after following these two routes of administration. Because dose measurements of DHEA administered transdermally have already been demonstrated, these measurements of serum testosterone 0 at 2 weeks 0 do not provide a reliable assessment of the actual concentration of no (E2) estradiol testosterone (testosterone). ) : intracellular estrogens and androgens

Labrie, Belanger et al., 1997; Labrie, Belanger et al., 2006, and Labrie, 2006.

Belanger, et al, 2007b. 1 We compared DHEA serum levels and 510105 known to be closely related to 80017098605, active estrogens and their metabolites. conducted a detailed analysis of changes in Vi hour serum steroid levels on the first day and after 2 weeks of daily oral and transdermal administration of DHEA with DEAH cream or gel”- Cases and Methods: Shall TU shared Healthy subjects aged 60-Vo in the study Subject to approval by the IRB and their informed consent in writing Body weight was 77080 + normal body weight according to Metropolitan Life tables No case had significant disturbance in metabolism or endocrine glands “disorder” or coronary artery disease or high pressure all anabolic or anabolic steroids androgens b sh did not treat any hypertension andy All participants had a medical history; anil Jal. at 1 months prior to detection of steroids comprising a comprehensive serum biochemistry profile; serum biochemical profiles and urinalysis; and detailed serum hormone determinations during the screening phase ( ald lipids, blood test protocol, study design, treatment and measurements - Y for each group. An open, randomized trial with written informed consent, and it was clear that the women were suitable for the experiment. Each case was divided randomly to receive (as) before breakfast for a period of (Lag) cases cals. By cream, gel, or by mouth DHEA

DHEA or; 791 grams of DHEA cream with a concentration of DHEA gel from the aha research clinic either; Oral concentration before breakfast. In “DHEA and before using andl) to 6 + 9” at Ase, then blood samples were taken at the hour of the first and fourth day (AVE 5 01 and Ves oY The first day of taking doses, as well as in the day and a half and two hours delay 3 and an hour dele ten and then obtaining blood samples at half Yo 1 1 cle la m cle le la cle la and 1 cle la and five cle la ¢ cle le and three DHEA 1 hour after giving YE 5 hours; Serum steroid analysis: Measured

DHEA, DHEA-S, androst-5-ene-3.beta.,17.beta.-diol (5-diol), 0 testosterone, androstenedione (4-dione), 17.beta.-estradiol (E.sub. 2), estrone (E.sub. 1), estrone sulfate (E.sub. 1 = S), androsterone glucuronide (ADT-G), and androstane-3*,17.beta.-diol glucuronide (3.alpha. -diol-G)

SNAY

1 — By gas chromatography and mass spectrometry (DHEA, 5-101, 4-dione, testosterone, E.sub.l and : spectrometry E.sub.2) using felectronimpact chemical ionization a [liquid chromatography] iONizati and liquid chromatography [liquid ch t hy] tandem mass spectrometry <DHEA-S) mass spectrometry turboionspray Ro1-5p ADT-G,07 (G - diol) as described: Labrie, Belanger et al., 2006; Labrie, Belanger, et al, 2007b and Swanson et al. 2007. —o calculations and statistical analysis on day 5 (VE) the area under the curve was measured for serum concentration per steroid)” between zero hour 5 Yi hour AUC) from zero - YE hour). The areas under the curves were calculated using the linear trapezoidal method (independent model). The relative bioavailability of DHEA gel, DHEA cream, and DHEA capsules was based on the mean difference in the logarithm of the transformed AUC values. All calculations were done using software (SAS Institute, Cary, NC, USA). ) SAS -1 Ye Results Oral administration of two 0-5 mg capsules of DHEA increased serum DHEA from YY + 7 nFaba mL to a maximum value of +15.1 Y.0 ng/ml at 1 hour, with a continuous decrease after that to 5.17 + nano-faba ml at 1 hour, followed by Als relative stability until YE 1 hour (Fig. 11a). When a gram of DHEA gel concentration 701 or 0 cream was applied to a 10 cm FX area of the groin, serum DHEA levels only began to increase at VY hour to reach The values of 7.0 + AY and 0.7 2A nmol/l, respectively, at Yi h (Fig. 11a). There was no significant difference between dally cream in terms of serum 1 levels. ae DHEA any of the time intervals studied up to dele VE after the first application of a steroid injectable substance to the skin.

_vo- for 5-Diol by mouth; Serum DHEA concentration increased after administration of 5-Diol when measured from 0.1 ng/ + 1.19 ng/mL to a maximum value of 0.07 + 0.71 pre-concentration. treatment, with a slow and continuous decrease thereafter to reach 0.749 + 05 ng / dele ml at -5 hours (Fig. 11b). It can be seen that in the same figure the levels of YE ml increased when transdermal by cream or gel to reach DHEA in the serum more slowly after the administration of Diol © + tg/ml of cream and 9 no,;14 + 0.060 to significantly different values of hr. YE ng/mL for gel at oe in serum of 0.7 + (564 g/mL) 4-dione by mouth; DHEA increased after administration of ng/mL at 1 hour, followed by a rapid decrease to values that remained YY + 9.5 to a maximum value 74 hours (Fig. A mL between faba nano1, 7 In the case of relative stabilization of about baie 0 on the other hand by cream or A©9, the increase in DHEA was observed giving anys (VY) (ng/mL 0) + CAs 1.0 + 0.9 h at first serum YE values; - Dione only at cream and gel; respectively. Indeed; After serum testosterone, a comparative pattern was observed for serum testosterone of testosterone increased cadll mg by 00 DHEA capsules of 0 ml at an hour. This was followed by an increase faba nano VE + 79 ng/ml to a maximum value of hours and followed by a relative stability thereafter T ng/ml at AE GT rapidly decreasing to a gel as a cream or DHEA gel an hour (Fig. 11b). When YE was used to ng/mL. As observed at 1.40 hours and of about YE value first observed increase by oral route or via DHEA (a) and (1b); The first administration of 11 (Fig. 0 hr. Y) skin had no statistical effect on serum levels of L 51 or 52 during the first serotype. A similar pattern was observed, although it slightly delayed DHEA-S. followed by gal dea of 508 mg after oral administration of two 5-Diol and DHEA capsules compared to mL faba micro 1 + 4 (Fig. 1 a)).Therefore, serum 0115-5 increased DHEA μg/mL at AE + 1.1 μg/mL at 1 hour to a maximum value of +0.1 to no Yo.

OV AY

-11- hour. No change was observed in YE μg/mL at 17 + 2 hours with a sustained decrease to 0.7 in the form of DHEA cream or gel during the first 4–7 hours after administration of DHEA-S (Lad). ,

Ve hours after the first serum YE does not change significantly during the first 51-5 (oil from the 0 hour side. ?ng / + VE which is a major androgen metabolite; from ( lad) ADT-G increased © ml at 2 hours and after faba nano 01460 + 01460 ng/ml at 7496 hr 10560 + 768 ml to gram/so + 11 76 nano hr g/ml at © + AY that decreased continuously to ml to faba increased from 7.7 + 0 nano egal h (Fig. 11a). 2 hours (Fig. 11b).So in spite of that the faba nano was 7.0 + 005

Tg decrease was observed only for ¢ADT-G slower than for G - diol -” ¥ the observed decrease for 0

DHEA by mouth. after using; grams of DHEA between 2 hours and 7 hours after administration of 6-diol-0 or ?ADT-G. There was no significant change of eskin on the skin (7 01 at a concentration of 11 hours). (Fig. No. YE to Lad for daily doses; it is possible to VE when the measurements of the same kinetic variables were repeated on the day + led to a pre-dose value of 7, DHEA mg of 50 observations Giving two capsules Vo ml at an hour followed by [DHEA ng 4.4 + 14.8 to a maximum concentration of cde ng / +f, a continuous decrease thereafter to 4.8 + 4,» ng/ml at 7 o'clock (Fig. 61a).No characteristic changes were observed (gel by cream or DHEA another Laie was administered; dea ml and 51 ng/ml after faba nano 01 serum between DHEA during a 74-hour period and remained 1 ng/ml after applying the gel. 11 applying the cream; and between 7 ng/ml and serum yo steroids per day 40 The serum concentration of 5-Diol Lae increased similarly; ng/mL at an hour with a slow decrease of YY + 0.717 mL to faba glee + 17 (Fig. 11B). As is YE ml at / aba nano 056 + TE After that, to reach -1.58 hours at approximately VE during the period of WE Lad (Diol) DHEA remained observable for the 'gel ng/ml after applying a gel = 0.7 0.1 ng/ml followed by application of cream and 0.1 Yo

OV AY

—vy-— steroid From taking shots; The serum concentration of this VE increased on day 4-dione measured at ng/mL and was followed by a rapid decrease of 0.7 + 4.8 ng/mL to a maximum value »,7 + 1.7 From YE ng/ml at GY EY ng/ml T hours at 0.1 + 1.8 to 1.8 ng/mL on the skin as a cream or gel; There was no significant increase in DHEA (Fig. 711a). After infusing ml at two hours with values that remained thereafter when the serum faba stabilized to about 7.5 nanometers (4-01006 © 4-01006) testosterone increased by 1 hour (Fig. YE ml until faba Nano 0.1 - 0.1 relative at

VY) of DHEA mg from 100 serums per day; 1 for doses after oral administration of ng/ml at 1 hour and followed by 11 + AY, 11 ml to a maximum value of nano fala 04 + (VY) h (Fig. No. YE ng / ml at 0.04 + 0 TY) Continuous decrease to an unchanged value during the testosterone period as a cream or gel Serum levels of DHEA remained after application 0 Statistical ANA hourly at about 7 ng/mL, this value was not different in terms of YE from the pre-treatment value. Ye during AVA or Fig. 2 (Fig. El) serum L levels by oral or transdermal administration. Increased DHEA for 14 times daily administration. mL to faba 1.15 + 1.45 μg serum from pre-dosing level DHEA-S 10 μg/mL 17 + 7.6 μg/mL at 1 hour continuously decreasing to 1 ,4 + AY serum DHEA-S hr (Fig. 91a) No significant changes were observed for YE at hr after YE during Lad 1-5 unchanged (gal On the skin. On the one hand DHEA after and Set by oral or transdermal administration (Fig. DHEA for $164 l ald daily administration) at a level higher than the day of serum VE started on the day of ADT-G that cpa in (B11).

YE nanograms/ml at 105 + 91 hours and VY nanograms/ml at 11716 continuously thereafter into the serum after ADT-G was placed one hour (Fig. 10a). No significant change occurred in serum levels of 0,0 + 11 ng/Y of 6 - diol - af J) on the skin. On the other hand, DHEA + 11 to 19.4 + 8.5 ng/ml at 2 hours to decrease slowly after that and reach Je Yo 100 mg from daily oral administration of VE Ball 1 hour after YE g/mL at SUT

OV AY

“VA serum after administration of © — diol - 07 No significant changes were observed in DHEA and DHEA metabolites to obtain a more accurate measure of the accumulation of (RY) across the epidermis (Fig. zero to its metabolite AUC, we compared the areas under the curve of serum steroid concentrations (values measured on the first and fourteenth day of dosing. As expected from VE (19), Figure 17, and Figure 17). 16) and Figure No. (OY) Figure No. (01) and Figure No. 0; (01) and Figure No. (91); Figure No. (VA) and Figure No. (VV) and Figure No. (71); and Figure No. (71) The estrogen number, except that the metabolites of the steroids (hours per YE from zero to AUC) were similar to the values of “steroids©” due to some accumulation of those (androgen 4) -diol — and 30 (ADT-G). E1-S) by mouth (Table No. (;)).In terms of DHEA to give VE on the first day and the day slower after DHEA and due to absorption of calall by other DHEA after 0 Highest given 8060-24 h given as cream or gel; 7100 or 787 dose values observed, respectively. 1 compared to day VE per day DHEA testosterone, 2, and E1 excluding os AY steroids also for each of the ef values that did not show this were noted: Table Yo dll of dose administration plus VE and day 1 Measured in the day 2000-24 h. Its values are -30| ADT|E1-S| DHE| E2| El]|testoste 4-1 - TANA 0 - 01011 -G A-S rone | dione| diol (nano (pico) a (pico (pico

SU) © (nano aba g/ (micro [aba g SU) SY SL) g hr/m pba ghr/ml) hour/hr/ pba [Rely dat g slic [ie (Md) Hours/HH (de) Hours/m (J (Jd ml) J (J (Hf)

SY AY

4- I took ver to give [gv] this ves|ves to VeAl to £0 for the samples) 0% first EO (YO) took vey. sg] ves Research Viol volumes of samples (YO) (T1)] | Yeh VY D th/A Js 4 g of 0 961 Cream Take Vey Daddy Ader ou, tag EAT] Yo] vey] TA Axe] Samples (AT) COW) CH] Eo) CO EM] OY] (EW) (TY) (TF) First take AVY] YY A[Yay| yyy Alak Elad Akhr va] Alal 116 samples A (5) Art) Ui) Abham Mad Um Ab) Ah A Hama Fourteenth Fourth 0 [PVC] CRY I SEE Al-Kara Laqral Atakhra I’m getting close or ten / unless

reply to

- «=

Va took [Ye] ANIL YY L KD YY L KD YAY [YAY] Samples [(£3) A (mouth) (£2) Abed good manners (Ag] (ol erb) AD First Take Last Avg] Edhla Lad Any VAT] Amv Any Samples A(20) EV (FY) Adam (YO) ED] A (AN (NO) 14th TY TE VAT code for tensile strength Val Tel VIL for the first tenth / first The values in parentheses represent the percentage of the coefficient of variation DHEA was given orally (XY 50 mg capsule) or postpartum On the skin l gm of 7010 JDHEA cream gm of 0 gel LS can be clearly seen in Table 0 and Figure YY. There was no significant change in the values of

h© 8060-24 for hormone 1; or E2 or serum testosterone measured on the VE day of dose administration compared to pre-dose levels. However, significant increases were observed in each of the other steroids. Thus, following administration of 100 mg of DHEA daily for two weeks; the area under the curve of DHEA concentration measured during the 24 hours following administration of 510010 was increased by 7131 over the initial treatment value while

- A _ and alpha-ADT-G (E1-S (DHEA-S (4-Dione (5-diol)) were observed to increase in both A and 7287 ZU 187, respectively. 6 - diol specific metabolites and metabolites DHEA for 8060-24 h ads Table © Primary Therapy

NE per day -30( ADT| E1-| DHE E2| El|testos 4-1 first —o| DHE| steroid —diol| -G S| A-S terone| dione A (nano (pico-A) pico

SUS) ((micr faba feb SY SG) dal (nano SHG] h/m and gram criminal field abal abalddfiely abs dal del field for h/ (J (U4 h/ |) h 11 VAY AVY] Yl Alera basal (initial treatment) 01 mg capsule XY (A) gov| praise Vv gl qo, | Vue for lapping avy] Day 4 Ak0 lah v 14th insomnia NT YY] NYY] NYY] NY finally Aha YY Fourth | Ten OV AY

—-AY— (b); g of 7001 cream

YYE avy] v, a7 104 Yo ALY] AVY] YY, Al ld y YVY the fourteenth day the fourth 0,7 to the father YN against the VY of to, a kar nar or ten (C); gm of 9600 GEL today YAA Aaa VYAe[ Avg] 1 Lama YAR Lara Umm Laban XIV

LY YoY, aT] Lecthra YY OY, ed IV 4 Agala Dakar Lak 10 DHEA was administered orally or through the skin in the form of a cream or gel. Basal h 8060-24 values were calculated by doubling the basal serum steroid levels of initial treatment Ly in that assay within YE h. Except for DHEA and F5-010; Smaller increases were observed following administration of DHEA© Reality Cream or Gel; After applying DHEA cream, the h value of 8060-24 for DHEA-S increased by 177004 only, while the values for h 8060-24 increased for 4-01008; (E1-S 01-6 and ?alpha - diol - 6 by OV AY

Name VY, VY, and 2774 5 AVEO for the titre, respectively. On the other hand, the AUC values of DHEA and 0a0a-5 increased by 7405 and 2717, respectively (Table co, Fig. No. (YY). Similar but less increases were observed for DHEA gel, where h a 8060 increased - 24 for ADT-G (E1-S (DHEA-S 4-0108), 3 “J Tod 6 - diol - Wi, 15 e075 37, © and 7270 for the standard sample, while AUC0-24 h ad for 5-Diol DHEA by 7749 5 ZY YA, respectively.Our recent results (Labrie, Belanger et al., 2007b) demonstrated that the Lad changes in DHEA observed following exogenous DHEA administration It reached an exaggerated estimate of approximately 7900 for real changes in the composition of the sex steroid.In support of these data, Figure YY shows that after 0 administration of DHEA in the form of cream or gel, changes were distinguished for (Lad) DHEA As an exaggerated estimate of changes in serum levels of all measured steroids except for A5-010, the immediate metabolite of DHEA, and for DHEA cream, the changes in h values 00-24 were not for hormones ( DHEA-S (4-Dione 1-5 1-6 3.alpha.-diol y serotypes are AVY, 4077, 2777, 2774, 2745 only A jie an increase of 74071 Vo from initial treatment serum DHEA levels. For hormones 800:09©61516,; Well-established 287 uridine glucuronosyl transferase (UGT 2815 (UGT 2B7) 2817 61no are the three enzymes responsible for the glucuronidation of all androgens and their metabolites1 in human SE (2003) Belanger et al. This recent realization of identification of all human UDT-glucuronosyltransferases |0 makes it possible to use glucuronide derivatives of androgens as markers with full 800009860 activity in both women and men : Labrie, Belanger et al., 2006; Labrie, Belanger, et al, 2007b and (Swanson et al. 2007). 6; the estimation of the percutaneous efficiency of DHEA for the conversion of Yo into active androgens at 757 when adding changes in 1-6 ram, 3 oY AY

AE (DHEA 4070 7). Similarly” after DHEA gel administration compared to 72771 changes (weighted value

Serological JOT 5 converts to increases by 705, 91, and 97 DHEA, the increase is 89 77 for the 1-6 (E1-S1 (DHEA-S) (4-Dione) hormones of AUCO-24 h only in the values of 2700 and sero-alpha-A010-6, respectively. In the intestine and liver, the level of glucuronidation is indicated because the high level of Lad formation is elevated for ADT-G and alpha-A0 (Belanger et al. (2003) G- Following oral DHEA administration; the relatively small increase in serum DHEA 1-5 (4710) compared to the 79709 increase in serum DHEA after oral DHEA administration indicates a relative potency of 777%. The conversion to estrogens hormones and as shown previously: Labrie, Belanger et al., 1997; Labrie, Belanger et al., 2006; Labrie, (01) who were given DHEA to women. The current data indicate that “( Belanger, et al, 2007b instead of amenorrhea androgens are often converted to estrogens (SU). Discussion “gel in cream or DHEA form.” Current data clearly show that during chronic treatment with Vo quickly reaches a level with no detectable change in Ster concentration oids, the concentration of each daily DHEA during steroids measured serum application of any of the steroids measured percutaneously; The DHEA is 1 hour after the first administration of YE to the skin. Accordingly; Starting with bes DHEA it stays at the same level” which thus indicates that the application of steroids to the concentration of all 0 skin maintains constant serum levels of DHEA and all its metabolites. and in women whose period has been interrupted; It is already known that the variance in the circadian rhythm of serum DHEA is relatively small compared with the situation in women who have not undergone menopause and have a normal cycle (1990). (Lui and Laughlin, oY AY

—Ao— No significant accumulation of DHEA The present data also show that following daily oral administration of either DHEA or its metabolites. Furthermore"; Skin DHEA metabolism is quantitatively similar; Quantitative differences are explained by enterohepatic metabolism following oral administration. Serum 5-01-6 5 ¥ alpha-Onc-6 combined with elevated DHEA for 8000-24 h © values after Oral administration of low 5-Diol 3 DHEA for 8000-24 h ad combined with percutaneous administration indicates that metabolism through the gastrointestinal tract and/or pathway I through DHEA-S activity into DHEA leads to an elevated level of hepatic conversion of hepatic 106-naNA (in addition to an increase in DHEA-SULFOTRANSFERASE et al., 1995) and its inactivation through the activity of enzymes and androgens hormones. J DHEA metabolism 0 Liver: glucuronosyltransferases (Belanger et al. 2003; Turgeon et al., 2001 and Hum et al., 1999) 144 ng hr/mL dE; As shown in Table No. (0), exposure to

DHEA of 001 mg on day 14 of oral administration for (AUCO-24 h) of 01097 ng h/mL and 407 ng h/mL AUCO-24 h leads to VO values After administration by (AY) and ?alpha-uh-6 in order. In terms of ADT-G for each of He (©- diol-) and alpha-ADT-G and DHEA for each of The AUC of DHEA Cream 7900 dermatologically is ng-hour/mL respectively. 114 ng-hour/mL; 7/47 ng-hour/mL; and 7 AUC corresponds to The value of DHEA hr / ml of aia nano 1 and a taste after oral administration » the ? 1 nanogram per hour / ml of exposure to (DHEA while after applying a cream) 6- diol-lf and homogenous androgensic . h / ml for the sum of the metabolites of the hormones DHA corresponds to 4 nanograms of DHEA for Oral route leads to a high level of DHEA conversion with Js giving that data and 2 alpha-onke-6 approximately ten times more than giving ADT-G to DHEA doing the same calculations for dey data by executioner; at least at doses that have been administered Use it. Yo need

-01- obtained after administration of DHEA in the form of ©0; An exposure to DHEA of 1 nano-aha/ml is associated with an AUCO-24 value of 7.1 nano-aha/ml for ADT-G + © Alpha-A00 -6; This therefore indicates a higher ratio between oral and dermal administration of DHEA. © As shown in Table No. ;; While the h value of 810060-24 for DHEA of 1 nanogram hour/ml leads to a value of 160 nanograms hour/ml of DHEA-S after oral administration. For (DHEA) corresponding values of YY ng hr/ml 5 19 ng hr/ml have been observed after sald steroid use) produced as cream or .gel so there is a multiple of 7-9 ,7 of DHEA=S in circulation following the same exposure to DHEA 0 in circulation (h-value 8060-24 for serum) after oral DHEA administration relative to dermal route under test conditions. The present data show a similar effect of DHEA passage through the gastrointestinal tract and liver on serum DHEA-S and 6-01mR¥ diol-all-© hormones. Although less difference is observed; Relatively higher levels of serum 4-Dione were observed after oral administration of DHEA compared to percutaneous administration of a precursor steroid. Therefore, oral administration of DHEA with a value of 1 ng h/ml of DHEA 1 AUC0O-24 h leads to an h value of 8000-24 for 4-Dione of 1.7 n grams hour / ml, while the values of 0A, + nano aha hour / ml and 0.11 nano aha hour / ml were observed after administration of DHEA as cream and gel in order. ceirculation, the conversion of DHEA to lef 4-Dione 0 is 7.71-7,700 times that of oral DHEA administration relative to dermal route.The data in the table shows that the h value is 8060 -24 L-DHEA increased by 7131 over the titre sample following daily oral administration of 100 mg of DHEA compared to baseline levels for the initial treatment, while daily percutaneous administration of L 701 g of DHEA cream resulted in Yo increased serum DHEA levels by 74607 and 7749, respectively.Due to the application of 500 mg of OV AY

—AV- mg orally; the assumption of sin; 001 Skin data compared to current DHEA use indicate that the oral route is 7.9 to 8 times more effective; From the formulation in order. DHEA used for cream and gel

Vou, in a study that was also conducted on women who had stopped menstruating; Oral administration of the mini in the maximum amount of serum hormones 0145-5 and DHEA mg from Yoo to 5

Je / and no,? ng Je / g gle (Je / mg V.00 in testosterone pH DHEA / μg / ml 560.75 g 11 after a dose of 306 mg and 10 μg / refill An examination of (Buster et al. 1992) showed that 0510 mg; in the order 0510 by ml DHEA after a dose of 1.9 increased Lad) 0145-5 impairment in the Yo hormone these early results That double increase. In addition, 11,1 serum to DHEA Lay testosterone only doubled in 0 measured to one-third serum testosterone serum testosterone af Lae was adjusted to account for two-thirds of the non-specific binding in radioimmunoassay; Serum testosterone levels remained within the range of physiological levels during the 12 hours following administration of a dose of (Buster et al. 1992) mg Vo. The similar differences observed between the administration of 17.5618.0-0 by DHEA directly converted from 5-Diol to the skin have been observed for actual serum DHEA intake. .hydroxysteroid dehydrogenase (Labrie, Luu-The, et al. 2000) increased by approximately 718 compared to the standard sample after administration of 5-Diol JAUCO-24 h dad, while increases of 77717 and 8177 were measured after administration of 5060 mg. (DHEA mg of oral 100 L approx. DHEA and gel mS of Yo in terms of AY) and according to what has been mentioned; Man is unique; In addition to some primates

DHEA producing steroids that secrete large amounts of adrenals including adrenal glands and/or androgens hormones and then to 4-Dione hormones that are converted to DHEA-S: peripheral intercellular ‎ intracrine tissues 5 oY AY

—AA—

Labrie, 1991; Labrie, Belanger, et al, 1995; Labrie et al. 1996; Labrie,

Luu-The, et al, 1997; Simpson, 2000; Labrie, Luu-the, et al. 2005;

Labrie, Poulin, et al., 2006 and Labrie, Belanger, et al., 1998. endocrine disorder It is therefore noted that humans, in addition to having very complex adjoining endocrine glands, are largely involved in the formation of sex steroids in tissues. DAY, 5 In fact; While the ovaries (Belanger, et al., and (1998) (Labrie, 1991) “peripheral sandrogens are the exclusive sources of hormone secretion of testes and testes 5 where olla) are the least; the matter differs In humans and primates mammals 05 generally LE or Lia active sex steroids The active sex steroids are locally synthesized in peripheral tissues; therefore target tissues are available with controls that adjust 0 according to local requirements metabolism sex steroids formation and metabolism of sex steroids during adrenal vigor DHEA-S, DHEA for adrenal secretion increases adrenal secretion years; maximum values of cyclic A are reached to 1 in children of age ranges from adrenarche

DHEA- 5s DHEA year. So the levels of the two hormones Yo 5 Yo in the blood between the age of DHEA-S actually; at the age of 70; 1+©881809 et al. 1994) in serum 5 VO significantly decreases from its peak values while 7700 in serum DHEA-S levels decrease significantly.

Migeon et al. (Belanger et al. 1994) and 10-year-old AS can be reduced by 795-5-/011] by the adrenal glands DHEA, and the 170-795 deficiency results in the formation of DHEA (21). .. 7 androgens during aging lead to a significant decrease in the formation of adrenal hormones (85116a). And such as Belanger et al., 2006) and 651:096175 in target peripheral tissues 0 This marked decrease in the formation of sex steroids in peripheral tissues may also be implicated in the cause of the emergence of a series of diseases associated with aging. Or androgens hormones to DHEA-S hormones (3 DHEA), the conversion of oS) as previously in the target peripheral tissues depends on the level of active estrogens, the various active estrogens in each metabolite cell type of origin and metabolism Steroid Genetic Expression of Yo-Bd Enzymes

(1991, 18506). elucidation of the structure of most tissue-specific genes encoding the upstream enzymes involved in the conversion of DHEA-S; DHEA to androgens and/or estrogens indicates rapid progress in this area:

Labrie, Belanger et al., 1995; Labrie, Luu-The et al., 1997; Labrie,

Simard et al., 1996; Labrie, Luu-The et al., 2005; Labrie, Poulin et al., ©

Labrie, Luu-The, et al. 2000, Labrie, Sugimoto, et al. 1992, Labrie,

Simard et al, 1992; Luu-The, et al. 1995; and Labrie, Durocher et al. 1995). The data showing relatively high levels of androgen metabolite 0 in normal women strongly confirm:

Labrie, Belanger, et al. 1997; Labrie, Belanger et al., 2006; Labrie, and

Belanger, et al, 2007b. Androgens play a major physiological role in women, but this role is not adequately appreciated. The decrease of 74.5% in serum DHEA that occurs in the age range of Vo between Tos Yo to between 40 and 50 years of age in women (Belanger et al., 2006) could strongly explain osteopenia. In fact, it has been mentioned that age-related bone loss begins in the fourth decade of life, and the bone regeneration cycle was discovered before the menopause: exactly premenopausal women.(Mazess 1982; Riggs, et al. 1981, and Johnston et al. 1985) and according to these results, bone density was lower at all sites examined in women classified as perimenopausal compared to premenopausal women. (1989, et al., , 516005609). According to these results; The changes in the secretion of 0007 substances produced by the adrenal glands precede the decline by about 10-70 years.

In ovarian estrogen secretion, which stops at menopause (Labrie, Belanger, al. 2006). It is important to realize that not only was a decrease in DHEA-S 3 Ladi DHEA reduced by about 751 between years 71 00 but a similar decrease was observed for serum testosterone (Says 200101 et al. 1995) serum testosterone 0. Such data also confirm that hormone replacement therapy using androgen hormones or (substance) producing substances for them must begin early at the age of menopause in order to compensate for that early decline in the secretion of substances producing androgens hormones. By the adrenal glands and the parallel 6-parallel deficiency in serum testosterone (Labrie, 2006) 0 androgens and active estrogens that have been synthesized in the target peripheral tissues are excreted target tissues are active in the cells of origin and very little proliferation of active sex steroids occurs; Which leads to very low levels in the circulatory system 6100181100. In fact; According to what was previously observed (Labrie, (Belanger et al., 1997) and confirmed in the current study; the most striking effects1 of DHEA administration were observed on the levels of glucuronidation derivatives of metabolite metabolites DHT in the circulatory system; more specifically, ADT-G and ?alpha diol--6, while no significant changes or very slight changes were observed in serum levels of testosterone, El, or E2. These topically active steroids were produced in peripheral intracrine tissues that possess the enzymes 00 genes suitable for the synthesis of DHT from the adrenal substances producing DHEA and 5-M01142 as well as the enzymes that convert DHT to inactive metabolites. ADT inactive metabolites and ?diol-1af that are also modified by glucuronidation Belanger et al. (2003)- In a recent study, daily oral administration of 100 mg of DHEA Des hab did not affect glucuronidation. serum testosterone or DHT while ADT-G increased 5 DHEA to a similar extent (Av = 796) (Arlt et al. 2001) veo in the og al study Serum levels increased before DHEA dosing -S is at oY AY

Women of postmenopausal age from 0.00 µg/mL to about 0.4 µg/mL

/ml (1998) (Casson et al.) after daily oral administration of Yo Yo mg of DHEA for 7 days.

Months. However, serum levels of DHEA and testosterone did not change; measured after YY hours

of AT giving DHEA a significant change. Another study indicated that daily oral deja of ov

mg of DHEA led to serum androgen levels

within the premenopausal age range (1992). (Buster et al

The current data clearly shows that DHEA-S has been transformed; DHEA in peripheral intracrine tissues

peripheral intracrine tissues specific to androgens and/or estrogen hormones

Active estrogens Jas can exert its biological effects at its site of synthesis with no release; Or just release a few copies of active steroids into the circulation.

Accordingly; Serum levels cannot be used for testosterone or

El or E2 as variants for converting DHEA into androgens or prohormones

(Labrie, Belanger et al., 2006) are actually estrogens; Active steroids are metabolised

active steroids metabolized in the same cells in which they were synthesized and exerted their effect on the inactive yo metabolites to which the glucuronidated group and sulfated sulfur were introduced.

They eventually diffuse into the extracellular space and can be measured in the circulatory system:

Labrie, Belanger et al., 2006; Labrie, Belanger et al., 1997, and Labrie,

Belanger et al. 2007.

Measurement of the associated metabolites of androgens is the only method that allows an accurate assessment of the total pool of androgens in women. It is likely to be hormones

5 showed a similar situation despite the need for accurate assessment of pharmacokinetic properties

To metabolize estrogens and identify their metabolites.

Example number?

oYAY

Clinical Trial: 01158 Vagina Physiological treatment of vaginal atrophy Subjects and Methods This study is a predictive phases ADE experiment; multiple; random ; Controlled dail gs 5 drug satisfaction mutually exclusive comprising 0 patients per class total (Yoo patient) 0 So two hundred postmenopausal women were therefore randomly assigned to receive Aah of the following concentrations of DHEA (Y,Y0) 70.75 jin ley (70.5 mg of DHEA) 1.0 (70.5) mg of DHEA or 11 mg of DHEA placed inside the vagina. The study was divided into two phases (¢ meaning more specific then aad) and was followed by a treatment period of 1 week VY. A. Absence of menstruation for at least 1 year; or B. Levels 511 greater than or equal to 500 mIU/mL (within 01 days prior to day 1) in women who had no periods in 3d greater than OR Equal to 1 month but less than 4 month AR OR 0 hysterectomized women who were of premenopausal age at the time of hysterectomy OR C. After six or more weeks (from screening visit) of bilateral oophorectomy - women who self-identify with at least one of the symptoms moderate to The following extreme symptoms: cilia 0 Vaginal dryness (not present; simple » moderate; or severe). Irritation/itching of the vagina and/or vulva (non-existent; mild; moderate; or severe). oYAY

q Ad —_ _ Vaginal pain associated with sexual activity (none; Jaren, moderate or severe). Women should be aware of the symptom that bothers them the most when starting treatment. This presentation will then come and evaluate the effect of the treatment. 2- Women whose ages are between 50 and 10 years old. Women who wish to participate in the study and who agree to sign a written consent. - Women with a small maturity coefficient (guidance fraction no more than 75 of the superficial WAY on the vaginal sample). - Women who have a vaginal pH higher than 0 Ve - normal mammography within 4 months of the start of the study. gd test normal. - A normal PAP sample (including inflammatory changes) within the last 11 decile (from day 1). For women who have had a coed hysterectomy, the PAP die will consist of at least one slice. 1- No previous or current addiction to drugs or alcohol. Body weight within the range of 18.5 to YO of typical body weight according to the body mass index (BMI) (WHO). Drug metabolism or .steroid - blood properties, clinical chemistry, and normal urinalysis at baseline. Yo - Negative serologic properties of each Negative serology of HIV/HIV2 and Hepatitis C 5 and. a

q ¢ — — The exclusion criteria from the study were as follows: - Undiagnosed abnormal genital bleeding. - A prior diagnosis of cancer, except for skin cancer (non-melanoma ©). - Endometrial hyperplasia endometrium with a live sample upon examination or endometrial cancer. - Less thromboembolic disease or a history of it Significant metabolic or endocrine disease Significant clinical gastrointestinal, liver or gallbladder disease 0 Recurrent migraine headache No RE with conventional treatment. Diabetes that is not controlled with conventional treatment. Significant complications when receiving hormonal treatment (Ga). During the 9 months before entering the study (check-up visit) 1- Using a progestin estrogen pellet injectable drug LK during the six months before entering the study. Oral or intrauterine treatment with 000965100 in the six weeks prior to assessment at baseline. papillary (episodes; types of cream; OR gels or transdermal estrogen 00 alone or progestin/estrogen products in the 4 weeks prior to assessment at baseline. oY AY

c q — patients can be washed as follows; However, the questionnaire for vaginal atrophy must be answered after the required wash-out period: A wash-out period at least weeks for pretreatment with DHEA (estrogen) and/or oral ceprogestin. Wash-out period; at least weeks for pre-treatment with transdermal hormones Oral wash-out period At least 2 weeks of hormone replacement therapy added topically to treat vaginal dryness At least 6 months of treatment with an estrogen ball or injectable progestin drug 8 weeks or longer of prior treatment with Jala progestin Uterus 0 Six months or longer for prior progestin implants or injectable drug therapy B6511017 alone Pretreatment with androgens and anabolic steroids within ¥ months prior to the examination visit Treatment Oral corticosteroid within six months of the start of the study. Or in the ears - Cardiac failure or heart disease Coronary heart is clear. Hypertension greater than or equal to 95/1768 mm Hg or not controlled by standard therapy 51800810.

_ a q _ - clinically significant depression, depression, or confirmed history of a psychiatric disorder. severe psychiatric disturbance yas - taking an experimental drug within 10 days of the examination visit. Relevant clinical abnormal biochemical or blood characteristics. Cytological characteristics of the cervix at the baseline showing limited low-grade squamous intraepithelial lesion (LGISIL) or worse. Smoking more than 10 cigarettes per day. - Taking drugs that interfere with the metabolism of hormones (for example, ketoconazole (Jil), action inhibitors, or steroids that interact with Jie receptors or SERMs -0, or appear in a test for uterine fibroma The known presence of uterine lymphoma - in gynecological diseases. Or when coagulation disorders - anticoagulant drug therapy. including a) total blood components and coagulation); cblood chemistry; and urinalysis at all visits. Serum FSH should only be measured in women who had not had a period for more than 7 months. but less than VY months or of premenopausal age at the time of hysterectomy: 0 levels measured

DHEA-S, androst-5-ene-3.beta., 17 .beta.—diol (5-diol), dihydrotestosterone (DHT), testosterone (testo), androstenedione) 4-

— q 7 — dione), estrone (E.sub.1), estradiol (E.sub.2), E.sub.1-S, androsterone glucuronide (ADT-G), androstane-3.alpha.,17. beta.-diol-3G (3.alpha.- diol-3G) and 3.alpha.—diol-17G. In serum in the Laboratory of Molecular Endocrinology, CHUL Research 06016 © using mass spectrometry as described.

Labrie, Belanger et al. 2006; Labrie, Belanger et al. 2007; Labrie, Cusan et al. 2008. Vaginal pH and cytology 0 for maturation index and Pap sample (PAP) All samples were examined by the same cytologist (Dr. aud (Robert Dube) WAN Diseases Hospital (Quebec City, Canada 0130]1-5 that was hidden from treatment regimens. Then x 0 cells for LIAN classification in a surface WIA image “(S) classify cells) as superficial squamous and squamous (P) parabasal sx Bll and adjacent ¢(I) intermediate and intermediate (Meisels 1967; Wied 1993) 10 By peeling the middle third of the wall vaginal smears the specimens were obtained vaginalis, the lateral part of the vagina using the rounded end of a knife with a flat tip of the model 76 /a / Then it was immediately fixed using cellular spray (glass slide dala) and this material was placed on a slide after that the samples were sent to the central laboratory 5. Spray-Cyte 0 Vaginal pHVaginal pH is measured by placing a pH indicator strip directly on the side wall of the vagina using COIS forcesps for Papanicolaou sample if not done in the last 11 months; Endocervix samples are obtained; and outside the cervix (cexocervix) and the vaginal vault and are fixed using cellular sprays. Samples were collected using an Ayre oY AY knife

q A — — endometrial biopsy Endometrial biopsy was performed at screening and at ? months at the end of the study. All biopsies were examined by the same central laboratory pathologist, Dr.

Robert Dube) Department of Cytology; Quebec City, Canada Enfant-Jesus Hospital (Quebec City, Canada Enfant-Jesus 0). Vaginal examination at the same time intervals for VY 5A LEY week; the gynecologist or study physician at each site performed a vaginal examination to assess risk (None ¢ Minor moderate or severe (using values of 0, 1, Y and A in order): for the main signs of vaginal atrophy meaning more specifically vaginal secretions | 0 colorl color [7180108] Vaginal cepithelial integrity and vaginal epithelial surface thickness As seen in Figures YT to YA A time-dependent, dose-related and statistically significant improvement was observed for all four markers of atrophy In fact, the beneficial effects noted by the gynecologist and/or supervising physician could almost match vo to those reported by the women themselves about their most troubling symptoms.The vaginal examination was performed at examination and then at day 1 and week 1, As, 71. Vaginal secretions, vaginal color, and epithelium integrity were evaluated. vaginitis” and the thickness of the vaginal surface epithelium according to the following severity scores: none; simple moderate; or severe. The definitions of severity were as follows: a) vaginal discharge 1 absence of atrophy: normal clear secretions observed on vaginal walls simple mild superficial coating of secretions; Difficulty inserting the endoscope. oYAY

Moderate: Moderate, very simple secretions that cover the entire vault of the vagina and may need lubrication using speculum to prevent pain. severely secretory not present; inflamed sore note; In need of lubrication using endoscope to prevent pain. © b) the integrity of the vaginal epithelium

No atrophy: normal. Simple: the presence of blood on the surface of the vagina with scraping. Moderate: blood on the surface of the vagina with light contact.

Vo severe: the surface of the vagina includes spotting that hemorrhagic before contact and blood on light contact. c) The surface thickness of the vaginal epithelium lacks atrophy: wrinkle and elasticity of the vault. Minor: note weak wrinkling, Poor rogation, and some elasticity of the vault of the vagina. moderate: smooth 5010017; With some elasticity to the vault of the vagina.

1 stiff: smooth; Lack of elasticity Elasticity Contractions of the upper Y/Y part of the vagina or loss of vaginal tone Loss of vaginal tone (hernia cystocele and rectocele d) Color of the vagina No atrophy: pink. Simple: lighter color.

0 moderate: pale in colour.

oYAY

_ \ a =

severe: translucent; Either colorless or sparkling.

statistics

Summary tables presenting a number of observations will be prepared; mean or geometric mean

necessary » standard deviation Standard error of the mean ¢ £90 from confidence interval (Cl) 0 Two-sided; mean, minimum, and maximum for continuous variables; The number and percentage of each category

For gynecological data. Statistical analyzes will be performed at the two-sided significance level 0059 unless

al otherwise. The summary categories will generally consist of dose levels for treatments

DHEA (satisfaction remedy) 30.75 dr. and 71 of 7 ia (DHEA

The main endpoints of the analysis will consist of the following:

0 Statistically significant improvement in the moderate to severe symptom identified by the patient as most bothersome to her. The severity of the symptom is based on symptoms of increased severity: none; simple; moderate or severe. These estimates will be analyzed using the values 0, 1, 7, and ? in the order; All patients should have at least one symptom at base rated as 1 or oF. The symptom of concern is vaginal dryness; irritation/itching of the vagina and/or vulva; ally The vagina associated with sexual activity.

Vo decrease is statistically significant in the cells adjacent to the base and a statistically significant increase in the superficial cells. Data are measured for the gestational age. The maturity value will also be calculated. Statistically significant decrease in vaginal pH The Intent-to-Treat (ITT) group will consist of treated cases

0 with at least one effectiveness evaluation at baseline and at least one effectiveness evaluation after baseline. Patients who received the wrong treatment will be randomly analyzed. This analysis group should be viewed as the main analysis group. For the patients in this group who will not

OV AY yy forward value for AT analytics exposed to observations beyond the baseline; The event will be paid. dalled from the group subset 08+ Protocol (PP) and the group consists of each protocol to it lat week without significant violations of protocol 11 completing the study during the time point of as You sacrifice effectiveness data. Major protocol violations will be identified prior to detection of study 0 blinding based on review of data lists and observation of reports of protocol deviations. Patients must receive at least 7,950 of the required number of PP study treatment requests present in a cohort in the period specified by the protocol for this patient; Based on the daily data of the patient. Days to Weeks Va 5 06 must to visit schedule: + ? days for the day PP that patients in a group comply and for patients who received the wrong treatment; who are clearly ascertainable by NYS AE 0 depending on their treatment; Provided that there is no PP of the treatment you received; They will be analyzed in the group as a support group to analyze other violations that corrupt their data. It will be the efficacy data set. From the test product Gl the safety set will be defined as all patients given any dose or satisfactory treatment); and who have no safety information available. All DHEA 1 safety data analyzes will be based on this group. The analysis will be based on treatment already received. Evaluation of efficacy PP analyzes will provide TT cohort Efficacy analyzes will be performed primarily on a supportive efficacy cohort. The main objective of the study was to evaluate the dose response to vaginal mucosal treatments in postmenopausal women with DHEA atrophy. Topical action of L 00 produced the maximum effect on vaginal mucosal DHEA specifically by giving them the lowest dose of DHEA. The common home that meets this goal in Antal) for 7” 80108. The effectiveness points 038 decrease and the cells adjacent to the base increase in Vaginal pH; and decreases in vaginal pH as physiological parameters) and include surface lee (these endpoints will be referred to as

-1

The most disturbing symptom for the patient, who will tell herself about vaginal dryness, is Vaginal dryness

vulval irritation and/or ally cvaginal zal associated vagina

vaginal pain at sexual activity (These endpoints will be indicated

together as width degree coefficients). In addition to these major endpoints; will be too

© Calculation of maturity value. The widths reported by women themselves have the following values: none;

simple; moderate or severe to analyze using the values of zero, 1, 7, and ? in the order. All must be explained

End points Statistically significant effects for satisfying medication; So no modification is needed

Statistic of multiple final points.

The main time point for the analysis will be the assessment of week 101 with further data provided for weeks 0 7? And the?; AS The change from baseline evaluation to post-baseline evaluation will be used for

Analysis as well as the difference using placental therapy.

Results

Since cells adjacent to the base, bale, are the dominant category in the vaginal sample of women who are in

postmenopausal age with at least one moderate to severe symptom of vaginal atrophy; (Say VO) can be seen in Figure YY and Table 6 as, at two weeks of treatment, the lowest dose resulted in

of DHEA (0.75 2) decreased the percentage of cells adjacent to the base by 51 + 749.5,;

from 257 to 771.5, while a decrease of 0.471 + 717, / 8 7 ced AL ZV was noted.

Using 70.5 and 71 doses of DHEA in the same time period.

and in the standard spall for VY a week of treatment; Decrease rates were observed by 4.5 (70,5747 (Pp) < Yo Altenner) (7) > (R + F (M < N ...)

using 70.75, 70.5, and 7291 doses of DHEA, respectively, while no significant effect was observed in

Satisfying therapy group at any time period.

Lay No significant effect was observed at 11 weeks in the placement therapy group on the percentage

For change in surface cells (Table oT measured increases of P=) 20200 + TAT

OVAY

A 1 TYY (en Y kar (kn) and kar + kar (h 51 .) are in ,7 and 721.1 of the DHEA groups, respectively. It can also be seen that at 2,5 7 of the DHEA dose 7448 of the maximum effect was reached in two weeks while in the two weeks (A) 774.8 and 799.0 of the maximum effect were achieved. At the dose of 711 of DHEA the maximum effect was reached 0 effect already in 2 weeks Figure YY shows the absolute values of the surface cell vesicle ratio at different doses of DHEA and time periods Vaginal pH decreased in weeks VY by 0.11 + 0.49 of VT + 7, + units in the placebo group (Table oT Fig. (YE) while reductions of 1" + p = 11 005 were observed), from 1,495 + 17 unit, 7*9 + 0 0 , + from 1,271 + “IY pH units, VY + 0.700 , pH units, 2 from 1.97 + 0 pH units, 795 , + 4 of 1,74 + 1,7 pH units in the 20.,75, 720.50 and 21.0 DHEA-treated groups, respectively (Table 7). The table notes that at 70.5 doses of DHEA, QE 770.1 and 7945.1 of maximum effect on pH 011 (reduction of 1,776 Vo pH units in 2 weeks and; weeks of treatment; in the order. On the other hand, a low DHEA deja of 70.75 AY only achieved the maximum effect of 7.5 DHEA in AY weeks. No significant difference was observed in the PH change between the two doses. 70.8 and 791.0 of DHEA at weeks Af and 1 (Table 7). Figure ad YE shows the absolute pH at 0 doses of DHEA and different time periods. All women needed to have at study entry one or more of the following self-rated symptoms of vaginal atrophy from moderate to severe: dryness; vaginal or vulvar irritation/itching; or vaginal pain during sexual activity. symptoms that women themselves identify as nothing; simple; moderate or severe analyzed using al safrou 1, 7 and ? in the order. YO and according to what is shown in schedule A in the period of VY week; The severity of the most troubling symptom OV AY yg has decreased

by 0.197 + 4.00 in the placebo group, VT + 1,717 , + in the DHEA group

by 76.70 (p = 0.004 vs placebo ); 1,516 + 15 in

+1,77 and (m > 0009 vs. placement therapy) DHEA receiving 70.5 from de send

4 In the group receiving a higher dose of DHEA (p 71 > 0.0008 vs. satisfactory treatment). Figure yo shows the degree of improvement of the most annoying symptoms at different doses of

DHEA and time periods. vaginal dryness has been determined; pain associated with sexual activity; and irritation/itching

The vagina and/or vulva at the baseline are cited as the most troubling symptom.

and in the placement therapy group; The dryness of the vagina explained the gestational percentage of the improvements that were made

observed by the study participants.

0, and as shown in Figure No. (YO) the improvement in the most disturbing symptom was already significantly different (0.0 04 = p) at 70.75 of the DHEA dose, and the estrous ratio of women who did not occur had a change or worsening of the value of 1 in VY weeks from 257.5 in the homeopathy group to 7797.5; And 797/.8 and 799.1 in groups 2.9 and 20.1, respectively (Table 3)

15 Improvements across two or three severity categories were observed in 771.8 women treated with LAY 755.8, 787.7 and 747.5 women receiving DHEA formulations with a ratio of 5.75 7. , 70.5 and 71.0 Jie reported this significant improvement. Only 7 women reported a decrease in severity to none in the placenta group compared to 717/5,770 710.4 in the same DHEA group at the same time periods.

0 to 7 and ?; a 5 VY week; At each study site, the gynecologist or clinical trial supervising physician performed a vaginal examination to assess the severity (none; mild; moderate or severe and analyzed using values 0, 1, 7, and ?, respectively) for the main signs of vaginal atrophy, i.e. vaginal discharge. Vaginal secretions The color of the vagina The integrity of the epithelium

a

vaginal epithelial integrity and vaginal epithelial surface thickness .surface thickness LS, can be seen in Figures YT to 79; A time-dependent, dose-related and statistically significant improvement was observed for all four signs of vaginal atrophy. © Indeed; The beneficial effects noted by a gynecologist or physician can almost be matched to those

reported by women about the most disturbing symptoms as well as the effects on the cells of the vagina near the base and superficial, and the pH (SPH) are objective parameters of the effect of DHEA. Figures 01 and 1 show the mean serum steroid levels in VE hours (the Calculated from af 8060-24 measured on days 1 and 7 of treatment) for DHEA and 11 metabolites

0 from a recent study (Cusan et al. 2008, 8506a). It can be seen that serum 5-Diol DHEA (and 4-Dione on day 1) alone increases significantly, but within the values found in postmenopausal women (Labrie, Belanger et al. 2006). (- Serum estrogens (E2) serum, 1 and 15) were not affected, as well as hormones.

androgens 10 testo) serum and DHT significantly increased. Table + change from day 1 in the proportion of parabasal and superficial cells during topical treatment with increasing doses of *DHEA

oYAY

-1 0 - 6.10 + Y,VY - A H A A + TO + DHEA zero / from D A YY: YY: vq,0 — A YAS —| «00+ Yq, 0— DHEA from 1. , +, OVE +, 00+ Dam +801 1 + Ymra $Y, ¢— + YV,A - DHEA 7,0 «00 £9 0 a + ¢0Y -1 + -,7; - 6.7 + 6,1 - DHEA from 006 mouth "dam mouth" a zaka a or + 0 IRS os CE 2 IN oc SI 174 IRR 1 SRS I DHEA zero / from ve lo) oY ex 3 + 7 + aga +, eV + 77 DHEA from 1. , 0 a vv A

YEE VE in (0.14 + cb + 7" DHEA from 1 06 0. q + rah VTE LAA YEE TEL tabh TY DHEA from 006 A SEM + Intermediate * During Treatment Vaginal pH in Vaginal pH 1 Schedule 7: Change from Day *Topical DHEA using increasing doses of VY (VY) Week A Dose 01158 ?weeks

-1 ja 7 from “,YY—|DHEA + to itch + EY Hala 01 vv A from both to Ved NYE AY -7 ara + 1 to ARE: DHEA 6 out of -41,. + Haggara Kal Ahtara Yo 1 + Ye DHEA 0 of 1-11 DHEA + Mar Hal (YEE), VA VEY 1 + YY * Mean + SEM Table A Change from Day 1 in the most troubling symptom of vaginal atrophy during topical treatment with increasing doses of *DHEA *DHEA; Weeks 4 Weeks 111 Weeks Safar 7 From Hekki Hala EE Hala Hala - Yo + TY Destitute 58 From Lana Hana Eva TE, Asara Hala AR DHEA 6 From Hkn Yok Ahtara Child | LV YEN YY respected Yok non-existent 0 of Te DHEA dog FAS] on TY knit for ee * medium + SEM OV AY yA

LSP

For treatment with zero (treatment Y in most bothersome symptom in 1 weeks change from day >- change treated in category (severe satisfactory DHEA); 0.75 70.50 and 21 from etc ..., Y= while change in two categories as 1- Moderate -> Mild -> None) as - N Examples of Pharmaceutical Formulations © DHEA product for example but not limited to Presentation Multiple pharmaceutical formulations using old active sexual compounds. The concentration of the active ingredient can be varied widely depending on what the steroid is for discussed here. The amounts and types of other ingredients that may be included are well known in the art. Example A - vaginal or oral tablet 0 Component Percentage of Weight >

I

SV AY

-1.4- Example No. B - vaginal or oral tablet Ingredient Percentage of weight M I sell it All) Whitepsol 1-15 Using DHEA suppositories base Lipophilic suppositories have been prepared Can be used Any lipophilic base (Medisca, Montreal, Canada). Cocoa butter 335 (but not limited to JE base)

Hexaride Base 95, Hydrokote, «(Fattibase (Dehydag) Base (Cotomar o

Suppocire, Wecobee, theobroma oil, Japocire, Ovucire, Massa Estarinum, or other combinations of the above.

Vaginal or topical cream Example No. C: Vaginal or topical cream Ingredient Percentage of Weight A A

_ \ \ «=

USP 40% Ethanol

0 from | 7 vaginal or oral gelatin capsule Substances (gal) of the sex steroid DHEA may be substituted in the above formulations. More than one precursor may be included; in which case the combined weight percentage is preferably the weight percentage of the precursor The word given in the above examples.

© The invention is described with respect to preferred embodiments and examples but is not limited to them and those experienced in the art will understand the practical application and the broader scope of the invention which is otherwise limited by the patent protections herein.

Claims (1)

-111- Elements of protection -1 Pharmaceutical composition for intravaginal administration; For use in the manufacture of a drug for the treatment or reduction of Lay) dla) with cases HEA Fund from the fe range of incontinence 0600106006 vaginal atrophy atrophic vaginitis lia cvaginitis vagina jue «vaginal dryness sexual intercourse dyspareunia and impotence “sexual dysfunction©” includes: (1) an excipient or a pharmaceutically acceptable carrier diluent; (b) VY mg or less at the dose of at least one of the sex steroid producing substances 0 which is dehydroepiandrosterone or dehydroepiandrosterone androst- J “dehydroepiandrosterone sulfate” dehydroepiandrosterone sulfate ¢«4-androstene-3,17-dione or (5-ene-ADNC-36,176) 0 estrogen A therapeutically effective amount of at least one estrogen receptor modulator (z) receptor selective. “- The pharmaceutical composition according to claim (0) as the substance producing sex steroids It is a dehydroepiandrosterone and the selective estrogen receptor modulator (Yo) is acolbifene. —Y Pharmaceutical package containing two containers (JAY) containing Each contains a pharmaceutical active agent; So that Spl) mentioned to treat or reduce the possibility of Infection with selected pathological conditions from a group consisting of enuresis, incontinence, and atrophy The vagina cvaginal atrophy atrophic vaginitis vaginal dryness <vaginaldryness | 0 Dyspareunia and sexual dysfunction include: (A) A first container containing VY mg or less in dose of at least one of the precursors For sex steroids, which is dehydroepiandrosterone J dehydroepiandrosterone sulfate. Dihydroepiandrosterone sulfate oYAY -11"- 4- or 1800051-5-8086-36,176-010; or "dehydroepiandrosterone sulfate" which is formulated to be administered intravaginally; and at least one androstene—3,17-dione. estrogen receptor. (b) a second pot containing a selective estrogen receptor sex where the substance producing sex steroids oF pharmaceutical according to the protection element sell ;?- and the estrogen receptor modulating agent dehydroepiandrosterone is steroid © .acolbifene Acolbiphene is 651096107 receptor oY AY Gb A 3 fda ox UE 'oa water # ue hour > term AEE m 0 x ra ana 8 6 ground sage ye RRR Mr Rest EC 0 - FE Han EE YAN NE a 7 Bal LEY eS Chas wa 4 4 1 = ala a 3 p8 bed] Ry tad g a x Pog, Ey a ¥ Na A “a 3 * a 4 ea Here i Ted 8 BN te 8 8 . For CORE RL PZ Amal and . A a a a a a a a a a b 3 Te 5 God 7 1 ay a b 8 sala, 3 aj 5 cor ERE iin. Risen: & pee Eg ny Semin: | Tseer Aya Aja La Ana L 4 1 Fed Ra i Sl After the doses {ota Ll B E 5 M L Y 8 8 Ajd Lewah SE Akh 3 A A A A A B Led 1.8 fos Lon ney 8 A YN A D : : ha 4 # 0 8 Cg 5 : § No SEE ak IRN the Es Pd & $ EN Fil § ye yen fox Ed B for 1 HK <> Xai A aaa I A L ME N H fa 3 8 = 1: A Ty Lor W A Mq 4 CN FR TR 0 JO J SE EN Al-la ge aa aa 3} | ERE Hy Fe + ni Wy + at B MAD A A A NG B Tg RS AS 3 : A and Msa 8 mn, 3 fe SCE Rest > 2 hi Lo : 03 x A 1 RR 1 0 . God BR ATTEND Ss: Te SRE EC 7 A 0 Mesh 8D # TET A Essen Gala TE CS ST Habash M LD A Alha +1 for ES pe & milli maqaf are the oie Ana Ayeb { wy Ral EE 6 Fig. 1 [ore w wa i SRF EE = ad ARR ag NEE 1 Ya cE 0 8 ie pe = iy Fe¥ 3 Res em Bow EMER 8 SEE LONER t ADAS ELA IR A 1 ! Cs Reames TR = 1 Yo tn A Sh REE EY HN HE a FN 3 33 : (I Sak NI 5 0 #1 3 1 Prd + x FATT { 1 3 i 4 3 “Ben, 1 #8 ¥ um 1 + Resin & 3 H H Fs 3 | JN 2 3 5 HI 3 vin OER oF H 08 LIER oo! a 5 by 3 1 ES 3 Ho 2 FR 1 1 SI a ha gy 1 l 1001l H TT Thais 0 + i 1 8 R + i 1 i * AN RC I TL CR i 4 LF Fe 3 3 0 PNR i a lj 3 5 mm q + my ' 4 ada s l I TR $d TN 0 l l > LI YT : rms vad Na + 7 + 0 x 1 PER alm a L rasa asst assay BE A 7 SO SOT #? Find loom: modal aad =3 b 3 rum 4 . i i vod i yoy i id 3 FR 3 = EAR Lobo ENE ATEN 3 NE tA Et TE DCH i Poy i ?: 1 Teg 1 to HD SE I 8 1 EE EV I 5 AN A 45 7 Kha Gab ¥ i HRN owed \ REI 1 i ey A + DZ RA E 3 Vd 1 id LA “4 4 1 yo a IW Except: M - Now bd ey NRCS RIF a BE 1 q 3 7 4 RE oY REC: te 3 + RAC foo 1d ALL S > By ¥ iF We i ¥ ol 8 0 J L A M L H i, 8 8 a a a ss 1. 3% 8 i wa a l 1 a 3 moe FAHEY + 24 Tg tS i Nd To wd Head ae BF & ha aam ha x Yorn. yl: 8 Shaq 5:73 a “mv B) 8 du | A K EO A £& RTE S Foe 3 A 1 - TO A A A 5 WW RENT SE RE. Ee LS SUS. SURE. ape WRENN REET E) 5 0 ki l ": i \ 8 we eo 3 J TA DA TA LA LA LA EE Ea SR ref F & Hash 3 A 0 ? J CE ES 3 and 4 ?? _ \ \ Aj A yo 3 CER Moan sda pdt 1 She gd Nb Lr RETR Yay RC Mov I Se Se Be pRER TRY 'JIN UR C B S A B JY : Tas a hi a be APG 1 << The EFI 1 B. 4B is 1 B The 1 A N Rar “3x SE I OE Ril + Mabeh is for AR Arr + Po Se pre | AL cleared ACER J, 5d hi * ee TE FS } 3 Fou : {i A 1 Ee the colon, 1 Ce omen] Lg : v Cy ES SE ats INE SL 3 0 mint I A : 0 pe a a a REE a NE 8 5 er' SE ARTY I SA: A 1 Peed aE YY TTT eel] tes LI + at. et Llab i Cast fe L EE BE A TS ER 8 A A Asher PE A LAY Amat A RED Fine Albo Aada EE EE Al Layl pad ae atl edt M Tong Toy Yor Lid fd avr a FRR J & A “iN 3 TN Ah HE? i H 3 SE 1 PI Ii NY + hi od. <BR Sn Te , Seo 1 0 N id Ss A A ti § 8 A ECS re EN Er Yb FRE N iol d Po Ted ether 8 18 CIE N N isd 3 Teh i i A Wad 100 : N & Rid + * 0 8 i NES ARLE a ¥ NDE aja 4 8 § i Ty 3 mn RT N N 0 lysa 8 8 : a ¥ a em v i + 1 1 ah 3 FER EN LET YEN JRC, SINISE? L 1 a IRS #under : L 5 1 NMA. Let TW 1 3 k FR IT x AS RE RSC A 0 3 . od AR L 3 7: 1 k T Lmam Alm Laman Misak Amad Imama Do not be pleased Sly ig 0G LAJ JI Asher 386 #2 Lakhh Jahh 8Jh |. £4 (with stats) Cn pdt after cheek Rg 40 TE Shape? NE COR i a aN RINT CR House ,. x rs dose 5 by nda 8 BE ton for cd SE EE a i eg 0 N : dl ah 0 i B ' N H eS H i Sd glossiness vd 1 : 7 bin 3 hi RR god {RIS and ks Sn h #*- d ha RHES k a . A iy oad AA A H RS pS : B G Ea 3 Ed A fo i i, 7 | 0 He Lee 8 i on, HE ] i 0 if i i 4K RCE A SUV SE FES ou a : Eo ie 1020 A Fv : 8 ... A WR A ONE x NF REET 3 3 a 1 1 > A 8 A m Hal Be i Rl Ld 3 i gd x 5 0 Log A B A H A iE 3 The Rant, Ee EI of Es fas, SH 2 Ree Walk aaa i i by . I'm not examining TA LA 1 FA D A A A KID xX. 8 Ais A a 0 A 3 Ba 3 km l + to J 3 m 3 | 6 8 a Foe 1 1 5 i 8 8 8 8 8 8 8 8 8 8 8 a for the six aaa aaa a a a a a a a a a a a a a a aaa aaaaaaaaaaaaaaaaa What is the value of the MM L 1 Magogite? Sh HT UE SUS.?” 1?; Reply and disclose g? 2c #8 Sedat A L A L A L A A L A L A L A L A L A L A L A L A L A L A L A L A L A L A L A } + id ¥ i i i i - 1 i : Was yesterday: od bg Tey en § ¥ lt “Ro, on Tuded ¥ EE EE Pn ER 3 3 4 34 nr Aaa al-Assisi A” TH 1 1 + 3 a Te Bg a a l aa Te Sadler Tee TRE a SY Lede OW SR RLY goede gi F) nd 1 FS “from HE x fp JRE a 8 4 Tn odin i & = sh [1 : D 1 4 NER : 1 ; Raa. L + Asmla C +: 10D ibd HN H al 8 Yoyo 3 a RE ALA WK bi ks 5 0 ESA SQS L ALA A 0 ; sub 3 4 yey 1 : 1 he 3 LCE H 3 ps WR rd 1: a R x 4 4 b 0 # | + EX: TT NE MAMAN et ES YEAS Yo 2 and 3? & ak Yi Jal A A L To Ma M Jd A L Aram iin bald dealt GAT time period 358) B Te p x * Shell ol SV AY 4-0105 I would like to give it to you on the first day 1 EE 1 Ma al-yo al-sa’i ig to my land 1 i alee 3 DEA A 3 al-H 8 & . Ey sid £30 rpEs, oot i i 0 wR A Maine: Spy H PP = A . i iN <a 3 aN tw F m F&O x 3 kh d a l l 5 i 3 y y l ab 0 8 a 0 ba let 1 abash a 1 <>” c z of The SE A Shir 5 EA ks 2 3 . ki NT Messah vn SIRE N 8: A 7 NRE eas T Tag pa HES 3 ao onl ¥ 3 FR A Th 5 Aha Alma Ila YT Mes L Rr 4 8 & a. | i to. s a a a a la + 1 aa i a a a a a la a 3 BS goat BT > * ay a 5 etc. 5 and 8 ا ا ا ا ا ا ا ا ا ا ا ا ا ا لـ اا ا ا ا ا ا ا Ln BT_YETY TES TAL ASSEN 3% RE SS TE UE 8 sg YT YOY. v8 [hours] anda nd after that stayed AONE Ae 1 Aa Ae Jes PE “a Tien Fay 3 A Fa I aN Ty be SE Aa | ae TOUS +1 Elleep TRH OB Lo Fao i Pog Ma i I I TE a | v 13 +103 Be by 1 ALA LA aaa i 3 RE Tulsa So 8 A § Sig, A vad Lin A IN BER (FS SR ae Se = A UE ST NN a. A ‎ lk NO SE ER a ee ne a 7 [Ha net + REE] 41 8 RR SRE * : : 1 3 2 1 SR 1 3 a . a I a 1 best ss b 3 name a a a a 3 Hold on IE La "Pry ¥ as Responds to A La A La A La A gr = A pA Har g A EE SE A $4 Say A 7 0:0 OT # *? final) for these inventories des Al-Zamtiya al 1 ِ ِ ِ ِ َ ْ َ ْ َ ْ َْ َْ َْ َْ * form 350101-55 CONN SIFY dtd ESE URL JER, [I yg 43# id Cai RES The Foil a Ve i agi SA 1 4 : t H Gem 8 a eek $id H LE sondern on THER YE H N oN BN - . 0" M Oh Faqamed N H pa ERE IR en ; 9 XFS Fa > Ei | i SERIE ST Dag A 1 Ya : +. Lao + Lt | 3 ” vy od FF Nop, 0 tae IN 8 > : ES yl $end gE 1 3 1 i AR TR B S 1 AMOA ADA LD LA BL AK SE A 8 AH AE 8 i A ERECT + AE L 8 A 5 vey ¥ ahhhhhh SS SH iy 34 Eg 0 t his his + 4 * FRR l n a hand AR 1 arr + h 3 pe ass i <0 ... 1 ه ا 41 + > i FELT Sa " 8 sut and surahs for the touch of Jesus, the touch of the CE SS CH 'fod Ee i { § wl Dak CEG i 1 : { 2 IS 53 Fads Al-Hala SOOO SS ANA ALL THE Aa ME SU ALS A?? OE ET SK M 0 X LS TE SE *# faite ELE PROSE SRE REE Eu R SER. RARER c 75 [Rt oe PRR + bur lal we Boba poll d + gel H 0 º : : 3 3 Ny i a 0 HI + amas a 3 3 3 EI a $e to 37 Hy t i RR Se T H N by 3 m H A “3 8 gy = R HET J SSN i Edi oe A Te 3 1 ES C3 IE oP Nak [IS FER A A A f ESE SE BC Cif H Es A NI RN Taya A Ara a 8 A 7 RE A 0401 A re eros ; ® L 8 1 Aja 4 X Sai Sahih Mahari born I 3 A 3 AA i 8 i Bid wd L 1 3 Fi A 1 i ; L i i l 1] i i Jo a Se SR ine 8 Hic ER a eats * SS ai Kita Sh CH ERAT a pr aay ARs oy &?? 4 a £3 x 35 k1#1. 2 Wounds [by squares] dab hand Raa gl E ERE 185 SV AY -11- TUE, what DHEA beds mtn to DHEA-S aja * “8 DA I 1 ° . ENA; NI i 0 A : I : | º SA leo 0" l 1 x | rE or 1 FEE. ml 4 0 #25 for 0 i OE RE 111 1am 11] 0 dae 1 1 a 1 8 ¥ > i A NA 0 A N N 3 NN 8 : N\ Ni 0 ; Yoh \ NN a \ 1 N NN TN N\ \ N be NLL NEF 1 1 1 E A \ NN \ 1 1 A 1 AARNE .RRRRD ln Lr Dare Be No, no, no, no, no (MRE MRE LOR) > Disney: $y 12570 Y 8 L to E - DHT TF 0" 3 ra I a L i i LE: a I. ANT : > : : WN \ 0 a i 4 7 no 1mm vi A ; vod i NRE, La Ld To Wal B FS 0 A La Ld To Wal B FS 0 A La Ld Sha 8 8 Aj 1 0 ] § > iN A Soro L Lae 8 0 8 D wl A | HE oh EE ا 1 1 1 8 1 1 1 ا NB i \ \ NEI \ LN N : \ \ \ Nl Has 1 8 sf 1 ba mir l m wa ie hs 1 lalish Lqq a wh wh t aaa -1- 1 without 4 § Ii Pe : ys — Jagat VW Diol EY - CADT-G | io vo diol =e = Foe G dsl £ ou] [lows 83 | ) 0 Ce rn z 3 NR : B 9 aem TY T o 4 | 5 / * + or a = 1 1 0 | I Cy 0 0 0 wel for Yoo ¢ Fl = i « rN ; at : 1 4 27 mo all 11 NE ER lca NN ia NYY A 1 NA AH H NI N H N NN i Ni NE i "NRX N NY NN NR { 1 1 0 \ ] PRE UI 1a: Plaiting LALA i we) SEE FE FE OW NON Fertilizer 1 1 Ere by EA Ar u ER AA | Bq a IN TB 20a b oT oS — = Tuy a 4 bq Bema a  3 l \ Tens  “-” ' ; 3 1 : 8 3 > = 3 : Plug 0 ] 3 N 3 3 H : Bd Ie \ 1 0 1 bin .oo B º i 0 a w 8 = ES IEEE B |" ] 2 ْ 8 0 + A L 3 N L L A L H 1 Been LIA Toa i NEN ads H N a i L N \ Cad L 8 pia NN \ . he \ \ 0 0 lmk 0 \ . 0 NAN £1 INN 1 ) | \ \ BER "iii a UNL NY NN 2. Row LD DN ey | Saqr pe SE RIE Tja Jord Sen 05 ri Qu Saqr ih BM basically and 1 R SU od SE i od BC : 05 A JED SV AY -11- 3 $a " i So \ ” 3 al ) eB aaa ra re 2 xxx a b" zero 1 rt 1 ' or DHEA CONC. (%) 3 format SV AY -\YY- = 5 AT AR] * 7 Bey 2 . H hi's day? A 3 > 0 0" HSE Een 1 0 D L Ea ai = A Bi BE A D 8 BE A 0 E a ai I. | \ ; ; \ A B 7 RRB \ 2 a In ran EE AE \ Lay HLT PULL - e l 1 1 3 1 i 0 : : \ co IE 4 ina 4 a l \ ¥ i \ ; ; \ "7 Ha 7 BE 2 0 inn Ven 0 iS IE EB BR i H N y 8 1 0 H i xX / \ IR ER EB BB d = 3 0 3 ~ H [w 0 0 1h, 1 4 code hr [1A] A ; THES ONY Sm A To Sk Va form SARA Al Musalli ($6 g/mL) DHEA 1 1 NL IB ki +f SFR DHEA album 0 gen except for © from Yn Yder Kiz DHEA Ad + Ahrad from Karam Tote So pHEA It is forbidden by means of q 4 5 : | H § H “Tammy: 1 9 GRID compiled as a . ba 3 ge 5 1 i io 8: a ay 8 Capes 1 . 1 ¥ 7 Wa Nina Aat 0 1 17 8 #£ . i 0 a d [ toy _ ce do ie i al Lee © — Zayoun al-Musalla and M hed 8 i Ba i k Bo iY 0 5 Ja Lois Bas TS LEN Tadj L L: E 4 yy ya Tt 11 form D L 1 = Dayoke sero (nano faim) Vey SPRY wD ? Addition free from DHEA cholate: Aloe Ved with 4 grams of DHEA cream, Petcare Hote ne 4 of DHEA Care Gel P01 1 RA from Ad A "YE L and Al i 2 | Is) m H I for then: 0 1 ".+ i Ne 1 a wa . 8 ol Rech § ne tja aa yjht {RU Sanity a ZEAE SA Array for a collection of 3 ya y ERE anne yr 1 ’c 8 8 . 4 * 0 ¥ TE KB by 35 * RR OV AY -11?e- Ma {a wo Sn Hy well EB 2 a wo Sn Hy well EB 2 a wo Sn Hy well EB 2 CAL ra 8 a + 2 * Sa 3 tefl @ fe 1 8 3 lil BS ef Yon i 310 A I JERE solution ¥ SEER SER SELLA 8 RES EE RN “ap VIE 3 Re woo OF 7 DHEA xylat 0 of them abad ys oe ye bahd l jeera $ Sun Qurum Faa b M Hot Procare DHEA is forbidden from gel wi BMA + A x . 7 i 0 i EL Seiad Ey a Al from: any { Ls {ai how much T Lal £ . Rl EET SE UES Ao 1 pHEA 0 PERRI § DHEA. bof vd ? 11 6# ++ * fig ?- i 5 ra Je :: 0 zl 8 calories from [A] St 120 £ 4 DHEA A N A A A A A FY dee 4-8 grams of a gel with a large amount of 00001 vo A RES 8 God fod 8 lo = To 0 a 5 8 5 and 00 Yo ; : mew ee I ss w sac eer a e a: l * l min na to oad . 3) Yd a ma 1 3 y Soy ~~ 0 that m l 1 NSE]. DHEA SS with Yok eR ; 1 i wy for 4 g of virgin DHEA gel ole ! : 0 Tead [0 py i Tid fod >< wo EEE 1 FR PE N Hi 1 : ae Cn oN 3 l vi a 58 i 3 aa bis RE ERI SERRE NES i. EER Ll 1 1 EG L EER ATE EAS 3 A 4 Mad § EER and ER RE Led A Wy § & 0 3 ERE 0 3 3 3 b ) 3 3 3 3 3 4 * 0 #? FA 014 “0 - Form 0 + Wade OV -1?/- g/ml wy ©-07 AD Al-Musalla 0 et EE RI Fi j 1 1 i 1 rey 1 a First week DHEA Vaud Art. 30 XT Qn Foond . - Vole oS 0 DHEA 2p Locust of 1 Be 1 P11 Jel Mk004 Poker part L 0 FE Be Tove 1 hb) ISI 2] SE 21 = 1 § 1 ak 8 i ae i J NE +: Wah Acre DC as 8 I ا ا ا ا ا ا ie A HO 1 iy 78 5 PE PURE TURE 6 SURE FR SPO { Al-Musalla (Na No M A 0 Is G- Atab 3a fe? FAS 8 51 a | Hh ) Iv 131i. $ ELLE at a 1d]: ELLE D: i 14 31 Bias bat ah lah id a . ah ana [lna d "- a l ow tt FHI J J J Th J a this a SiS in Jdua' 34 17 1A 1 ve form OV AY —VYA- (Js Al-Mutassalli (Nano Grams) 01458 at LA 2a ink] Cn] rt a Ye 5 DHEA as a laxative ot Fe XY sels [Pete Karam Maiou Bakr pi © FD vol | Tolls Petcare DHEA on 6 locusts of Gel I i 0 ml 1 . ie 8 b but S | B eed STIR, solution HES + = ON SH Qing 2 a , 7 77 R Seed 2 PER § 4 i : a file b © - diol contact (Nano hi vit] HET 1 1 11 | x a Pligg shone SR Sry LET CO l 195 sn 3 n a 1 d 3 ; Te gy © . vy 1A 1 13 Fig. SY AY -?? + Pf 7011 bubble gel gradm for E & 1 1 14 S $ $ HE id Qo . CR, 0rd a o een a 1 + a thousand and hurdles. a" Ti Badd 1 a 3 et leshto ped wab al-musli bc a | ¢ : ml { $e LIN 1 3 3 + a TR TH dy — A: words to T LA 1 | to 8 2 D "+ and vy YA YE" * fig. 10 oN AY 1 pm Do. - pg io Fa 1 mg m 7 ml i i il a E, i AT 8 secret si today Ts Sw of I for 1 Fa, 1 8 TT d a la i.e LIE. oS 1 AA TE] tg EE Ce JY. TOE 1 : LA LA LA RAAT E # coherent - Yeo 1 s + 7 3 LEAL & LA DHEA Naud Te XT cm ow DHEA lum +4 locusts Sharm AB vp. 7515 AT CR DHEA gel bond C* + nickel A $A 1 td A Lima I oo ta isla Sey dal ow {J 8 for FoF 1 bed Fault Pn aq ha: 1 a: ty LR Hoo a ETT 8 + ah mah ; PETTY b mg uncle att + a: AT i AIR A FRE ARERR mB Aa Na Laba Ada Bram els Ga 5 HN Yua Ma H : 1 B 8 H BHEA i pens Ld a Da x ¥ ware i I] 0 1701 Ram from Qara Fuqun Badr 6 CR H N - - R : . + : 1 Tele 30 DHEA Locust gel bo 0". +. Ra Ben In Ys YA format SV AY -1?- : : l 1 do oo the DHEA-S 1 serum (5a g/ml) a Jt 1 0 b a 30d! 2 to aul ied : sq l Jub a I lazy ty be BHES E > % B A B 4 haram from SS Fqn Sa frame 1 1 the "H fot 4 t mala m a l hai Jil Makayu Barak Touq TUL I" ] ; Hy : 8 2 1 : of ] 0 8 & TR x 1 - for the i ¥ 1 i x TL 0 Vos to le + i 8 flashes by EET Masaf L a b %E h TAY m l ven ya ad . L B 8-5 Al-Musalla Sey Haram ML Los 0 º > He 7 1 H H EEE I Lat BOTA Leen Mi A 8 goed A 1 Jase. yoo SPRITE] op for 8 03 1 ya al dd ala 1 4 XK 3 vol bid i.e. a min lazy DHEA a duck 1 gram from Fotis oF DHEA ad kham - i haram bin Focusing Gel M. ® +? SE ET fig. 14 1- 2 0 1 Lt Jr I] > Al Musalla (NG, Is) ADTG Baa Ten os Al Boua Ye DHEA Fe} Y from Sila [LS KK Y anes § LINE 8 y p 1791 Kerr DHEA a dose of cr 8-9 moa J 1 and 51 gm of DHEA gm 4 locusts per gel = Yn : + Coa 1a fos Lakan 4 : L 18 Yao 2 ,: Be. C. Dala Maweda 8: Time in hours, gb sib b a * 3 PY 4A 4 (fale $6) The chapel Grider 3a b fed ; From kilat just as him? TRIG FOL OR 2011 DHER POOLS Locusts from Crimea 4 <3 HE ; 5 grams of Sun Gel 0088 Berker 010 wk tc Tag 3 aye oy IEE SI Pov Gl ) The Ha : : RECS a HN 3 Be “as IEL Mag 1 1 Tt, Ka § aol & he Ve TY + 2 ERE ERE mn ma 3 ELE art 2% ERE 2% I SR Yo form SY AY hums HN ~ Ud 0 oan 1 2 5 1 1 8 td Habson Helm Hajj horses i 1: 2 ’ HE Led ANTE ; Ud 0 A 5 B Ye cand tl Creed i BY or 1 ] 35 4 Tad Ey 0 HN | < A 1 QF the ng 1 k id 3 g LE i pos aa woe yon az © 1 4 M w yon 1 td ™ 3 b H «5% Lad pa b i A ES b Xe = 3< a : ar Bcd = Hl yo FY su a 9 FEE td Hl tl Hl 13 d Pl Hl 13 1 en 13 { i 0 8 i i i | 3 8 8 1 24 i = HI i Hl 8 Lk EI iT id id Pi H RE a 13 td HE HI ii Hl 8 4 4 = {IEEE of i3 Pl HE HN HE 7 7 83 4 << Pl Hl 13 by 1 ; id id i 8 3 g , FA 33 7 7 HE wi x $3 vod 1 1 HE er] 3 aN 3 oa yom ro HE NS i 0 for :1 Vi 13 RE a 4 J i HE i 5 A : id LE 0 Aj El Toe yarn 7 13 bol Hl PoE HE 13 0 © Alma A A A IE SE 1 13 HE i HE 8-7 3 The EERE 13 BH 1 13 0 1 A HE PoE : Met "1 Vii ol HE HERE Pom No Cod ETRE : i3 Po PO Fo AE HS : : 8 1 aid 1d 13 Po Pode Ah er FER SHEDS i {hs 5 i3 boli HEHE ETA Hs EEE HE: {iE Poa for i FEN JPN 5 7 BE 1 Lees emp 1 LE HEE bs 3a Ze 1 = a a bs 3a Ze 1: TOWNE ERLE J cE EEE word for wd SAR ORES: HIT oli = i d alma 1 so ta: except: fe, SAE EEE HERES MRA 1 LTA NS A EE THE I TA !4H HEE Dn SR oo 0 I PWN PERISH SE {iF RI ae: THORS : [SSE 00S BE tt FE {oH we Pore 1 redes H 0 S01 22%: SER!: Ga: BE Re Ml D DE Za Az D din POSE OE Hh i 3% NRE Te NEM RH 1! No 1 7 A lat 127 Weds DIT: 3 m 550 {: st ot Lt Ed 1 A Le A: Lee iain EE B A Rai as ya mt Ed REE 1 REE 1 ok HEE [ae IR ati cy BRR BE IR Rd Fresco 1 I ERS 8 RR RR A SR 2 0 EE for HIE EERE TC - BERR l la iE wo AT 8 1 2:1 HRY wi { 0 a TRE ERX) a 3 i oe 1 moa 1 A: A: A A | EE EE SN I 5 1 eS : EEE | Allah: A Na | No Alma EE A RRs L A ! IE: lat ERE | A VEE LEA head | HERR 1 GLEE LEE LEE LE AA 1 TRE GEL ERR HA NT LA oR sa pit LL SE LAGER AA: AA 4 Laman Gala 8 RITE 2 NR TL LEE Rubber machines: for 1 L ERE | B 8 0 32 HE SURI AA L Se FA SE! brackish pulp ew | Bt OE Al Hadimina A L qraa 8 © Sakea + < hE : ِ VBRES Jems Load LEA J+ A: JOE : [aR x) I rr EVEL I NE te &; h{: ¥ 1% A LIES £3 i yum oy § pied 0 hy MA aR == ES ne 1 i aan 3 EE Poo = ] Bay 0 4 SLT ey 5 - Sos comment for © = = } =n NL = = = R= = = = = for mag ae RE what DR A the A i, a has for d am 2 RES. No A Et = 3 IEA Br oeeeveE = wa BES aN yama d t + ha aa a | Fa A ¥ mae 5 wn Yea ham ala alha - la la lama OY * = EN EN a EE nm bod A Le terres 1 SN RI oe SON wag 2 Ides RRA 7 BN NCL I 7 0 J eS NS | hey TRE 7s ONS: NET 77 ANS an CONNEC DALA ¥ B= HAM LADK THAT TA EEE KHALJ JANA WEE POA {0 Era RN set Onn Cored EH SS aN AN peti 4 SURE: NN for Es 3 ; LUNAR SPN Sv St SNC BRR HEE Winter SC RMN: ALS Tennis: we Towers [mee | DHEA wa TY form OV AY _ \ Ad ag ag Ye 1 FER 3 Y 0 BH 5 Guin} i.e. “hunger scratch dam” : y FL + 1 A aa i ¥ Eo whatever * a ler find ld : RE NEE § & p. T 1 ] ¥ i i NE d dd BA ° : Sey 3 LBJ - 5 LEARY : D 117 TR SF 5 A exes sR PENG 7 Co A 3 1 8 the aE ec RA A: F IER SAN B ¥ ARTI [IRR 0% A Eee A: BLA FEE L 3 a the rn Sa ne Sea I BNE ee ZN EE os Yah T ey LAND BR Eo Nn Sa H RR REIN ES | TR ER and Kia i a La i 0 . LIE. T a nt Ae: | A ny > Aa i A 7 EEE aaa Po Sag HIE Sa CLE A SEE FN HE Slo tl RI 2 IN nN 1 d a 8 Aa Aa STAY JR SE Ne Lat Tia CO ES FE 20 Sa [RI hs NN Bete 3 PR HIE SEA A FEE OR Er Alya Lo TR ay Ab L xP L L L L L RN 0 A We FRI SN BR PR ls LE 3 0027 555 SN ERAN ER S20 Aja A 727 SRN RENEE Cr hie: Ea | PE SN 1 ¥ TER SoC NR FIRE C0 RON Sir | | i HE aN Ry 0003 St ROR) FREE St SN FO | 0 Po ho ARE ERENT eS ae TT ee Eo es RE EER A So La BS a pried NRE Lr NN Kadadah ERE 2 the ow - Soo EO ECE LEIS 0 aa wn Ep 00 HEE Se SAN a HIE Sd Son Se | 1 RAED Ga bast 33000 WN i i SE SS NO SU WIR sess SIE 0S NN er FOI vue: J 20 SS SA UE SS A Sk 1 A Etc Sie da ww a N M 0 Yo Wd Sr i Yh .- H 63 DHEA dosage form Ye response to -?- + Al-Habadaru Jenny Yo. | vo HN 3 h 8 and 0 + 1 d © Jah Heim ; ad a a bry ¥ = Co a = , a ;3 Bo = 3 over = 4 = a : 1 80178 NN = : 5 : = Ry 255 IANA a a = 7 0 5 = A no A Se RS a i | 3 =B ST = = BR Ga AE Soo OR 5 | ERE a ¥ — % with me oo ] i EN A cad ; AFR 0 0 z we LE CERN 1 RE = HN BEA = E 01 = 0 27 B A A | LAG Se 177 dey T Es 1 3 7 a alha b 5s a 3 oo BRS 7 A Ne vow J i en Rides Hy z z = aaa ERED Tk SE ] ER AR 1 i vey l cm ZN NS a bss aN = 2 = q a ja 0 ?* R Ee NN ji Cy or Litna i Loki Ba IRE sep a Fs oe EA: SEN a CA 3 0 h a EOE 7 ANE a 1 720% SAN i i Ban nN Do = 1 a 2 i — 1.0] [0 No 1 3 a m = b 8 = poe Na EE fos i po & x > en REN ee TE or 3 Roy — 2 8 m. 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ADT 3 GY agai AE 8 7 The validity period of this patent is twenty years from the date of filing the application, provided that the annual financial fee is paid for the patent and that it is not invalid or forfeited for violating any of the provisions of the patent system, layout designs of integrated circuits, plant varieties, and industrial designs, or its executive regulations issued by King Abdulaziz City for Science and Technology; Saudi Patent Office P.O. Box TAT Riyadh 57??11 ¢ Kingdom of Saudi Arabia Email: Patents @kacst.edu.sa