RU2234920C2 - Administration of androgenic steroids to women by non-oral route - Google Patents

Abstract

FIELD: medicine, gynecology.

SUBSTANCE: invention provides compositions, methods and application for the improvement of woman's health with enhanced or significantly enhanced levels of sex hormone-binding globulin (SHBG) and receiving additional estrogen by non-oral administration of androgenic steroid in the effective dose. Also, the invention provides compositions, methods and application for the combined administration (co-administration) of estrogen given orally in the effective dose and androgenic steroid given non-orally in the effective dose in women needing with additional amount of estrogen. Invention provides functional levels of androgenic steroids in women with enhanced levels of SHBG and, therefore, the improvement of their health.

EFFECT: valuable medicinal and physiological properties of steroids.

31 cl, 2 dwg, 4 ex

Description

Related Applications

This application claims the priority of provisional applications for US patents with registration numbers 60/138851; 60/138854 and 60/139323, each of which was filed on June 11, 1999. Each of these applications is hereby incorporated by reference.

Field of Invention

This invention generally relates to the administration of androgens to women. Thus, this invention includes the field of pharmaceutical sciences and medicine.

BACKGROUND OF THE INVENTION

It is known that the functional level of androgen hormones in women stimulates sexual health and sexual activity, feelings of well-being, maximizes muscle mass and function, and inhibits bone loss (osteoporosis). Further, the functional level of androgen hormones can stimulate cardiovascular and coronary health, reduce breast soreness, reduce vasomotor instability, modulate immune function, enhance some cognitive abilities, improve urinary tract health, reduce side effects associated with estrogen replenishment, and provide direct neuroprotective effects.

The achievement in women of functional levels of androgen hormones, such as testosterone, can be affected by the concentration of sex hormone-binding globulin (SHBG) in the serum. SHBG is a protein produced by the liver that binds sex hormones such as testosterone and estradiol in the blood. SHBG-related sex hormones are usually “non-functional”, i.e. unable to exert a biological effect on sex hormone receptors in target tissues and / or undergo clearance from the blood.

Orally administered estrogens increase serum SHBG levels. Serum SHBG levels also increase under various conditions, such as hyperthyroidism and pregnancy, and under the influence of certain other drugs, such as anticonvulsants. Elevated levels of SHBG alter the levels of androgen hormones and the doses required to achieve functional levels.

This invention provides methods, compositions and kits for achieving functional levels of androgenic steroids in women with elevated levels of SHBG and, therefore, improving their health.

SUMMARY OF THE INVENTION

Thus, this invention provides a method and kit for improving the health of a woman who has an elevated or substantially elevated level of sex hormone-binding globulin (SHBG). In addition, the present invention provides a method and kit for improving the health of a woman taking an additional amount of estrogen orally. Further, this invention provides a method and kit for improving the health of a woman in need of additional oral administration of estrogen.

In one aspect, such methods include non-oral administration of an androgenic steroid in an amount sufficient to provide a therapeutic effect in the presence of elevated or substantially elevated levels of SHBG. In another aspect, such methods include non-oral administration of an androgenic steroid in an amount sufficient to provide a therapeutic effect in the presence of oral administration of estrogen. In yet another embodiment, such methods include co-administering an effective amount of an orally administered estrogen and an amount of an non-oral administration of an androgenic steroid that is sufficient to provide a therapeutic effect in the presence of an orally administered estrogen.

Examples of specific androgenic steroids that can be used include, but are not limited to: testosterone, methyltestosterone, androstenedione, adrenosterone, dehydroepiandrosterone, oxymetholone, fluoxymesterone, methandrostenolone, testolactone, pregnenolone, nero-olone donol-nestro-nenone-nestro-nenone-nestro-nenone-nestro-nenone-nestro-nestone-nestro-nestone , androsterone, nandrolone, stanozolol, ethylestrenol, oxandrolone, bolasterone and mesterolone, testosterone propionate, testosterone cypionate, testosterone phenylacetate and testosterone enanthate a, testosterone acetate, testosterone bicyclate, testosterone heptanoate, testosterone decanoate, testosterone caprate, testosterone isocaprate, their isomers and derivatives, and combinations thereof.

The amount of androgen steroid administered can be measured in accordance with several different parameters. In one aspect, the amount of androgen steroid administered may be sufficient to achieve a therapeutic effect equivalent to a total serum testosterone level of from about 15 to about 1000 ng / dl. In another aspect of the invention, the amount of androgen steroid administered may be sufficient to achieve a therapeutic effect equivalent to a serum free testosterone level of from about 0.5 to about 30 pg / ml. In a further aspect of the invention, the amount of androgen steroid administered may be sufficient to achieve a therapeutic effect equivalent to a serum bioavailable testosterone level of from about 1 to about 70 ng / dl. In yet another aspect of the invention, the amount of androgen steroid administered may be sufficient to achieve a therapeutic effect equivalent to a dose of testosterone of at least about 50 μg / day.

Examples of specific estrogens that can be used in connection with the method of this invention include, but are not limited to: 17β-estradiol, 17α-estradiol, conjugated equine estradiol, esterified estrogen, micronized estradiol, sodium estrogen sulfate, ethinyl estradiol, estrone , tibolone, selective estrogen receptor modulators (SERM), phytoestrogens, their isomers and derivatives, and combinations thereof. In one aspect of the invention, the amount of estrogen administered may be a dose sufficient to achieve a therapeutic effect equivalent to a dose of conjugated equine estrogen from about 0.2 to about 3.0 mg / day.

Various forms of non-oral administration of androgen can be used in accordance with the methods of the present invention, including, but not limited to: topical administration or parenteral administration, or a combination thereof. In one aspect, topical administration forms include, but are not limited to, transdermal, or transmucosal, or sublingual administration forms, or combinations thereof. In another aspect, parenteral administration forms include, but are not limited to, intramuscular injection, or subcutaneous implantation, or a combination thereof.

Progestin can be coadministered with an androgenic steroid and estrogen, if desired. In one aspect, the administration of progestin may be an amount sufficient to ensure endometrial safety during administration of estrogen. In another embodiment, the administration of progestin may be an amount sufficient to provide effective contraception.

There are many indicators of improved health that may occur as a result of the method of the present invention. Of particular note, without limitation, is the restoration, enhancement, improvement, or prevention of characteristics such as sexual desire, frequency of sexual activity, stimulation of the genitals, the ability to achieve orgasm, pleasure during sexual activity, vitality, a sense of well-being, mood and a sense of emotional health (well-being), shyness, cognitive abilities, muscle mass and function, body composition, bone mineral density, skin and hair, pubic hair, genitourinary atrophy pathways, vaginal dryness, dry eyes, autoimmune health, vasomotor instability, breast tenderness, symptoms of premenstrual syndrome and combinations thereof.

A brief description of the graphic materials

Figure 1 shows the change in the level of total testosterone depending on the baseline level (background) of SHBG during application of a transdermal (transdermal) patch with testosterone (nominal delivery of 300 μg / day) to patients simultaneously receiving transdermally estradiol or orally conjugated equine estrogens.

Figure 2 shows the change in the level of free testosterone depending on the baseline (background) SHBG during application of the transdermal (transdermal) patch (nominal delivery of 300 μg / day) to patients simultaneously receiving transdermally estradiol or orally conjugated equine estrogens.

Detailed description

A. Definitions

The following terminology will be used in the description and in the claims of this invention.

Singular forms with the indefinite articles (“a”, “an”) and the definite article (“the”) include plural references, unless the context clearly indicates otherwise. For example, a reference to a “transdermal patch” includes a reference to one or more such transdermal patches, and a reference to an anrogen (estrogen) includes a reference to one or more such estrogens.

“Sex hormones” means any hormone that affects the growth or function of the reproductive organs or the development of secondary sexual characteristics. In one aspect, sex hormones include, but are not limited to, androgens, estrogens, progestins, and other hormones that are known in the art.

“Androgenic steroid,” or “androgen,” means a steroid, natural or synthetic, that exhibits its biological or pharmacological effects primarily through binding to androgen receptors. Examples include, but are not limited to: testosterone, methyltestosterone, androstenedione, adrenosterone, dehydroepiandrosterone, oxymetholone, fluoxymesterone, methandrostenolone, testolactone, pregnenolone, 17α-methylnortestosterone, norethandrolone olanedrolone dandrolone dandrolone, androgen, bolasterone and mesterolone, testosterone propionate, testosterone cypionate, testosterone phenylacetate and testosterone enanthate, testosterone acetate, testosterone bicyclate, testosterone heptanoate, decanoate estosterona, testosterone caprate, testosterone izokaprat, as well as their esters, derivatives, prodrugs and isomers.

“Testosterone” means a compound having the names IUPAC (17β) -17-hydroxyandrost-4-en-3-one and Δ ⁴ -androsten-17β-ol-3-one, as well as their isomers. Testosterone is listed in the Merck Index, entry no. 9322, at page 1569, 12 ^th ed. (1996).

“Estrogen” and “estrogen hormone” means any substance, natural or synthetic, that exhibits its biological or pharmacological effects primarily through binding to estrogen receptors. Examples include, but are not limited to: 17β-estradiol, 17α-estradiol, estriol, estrone, and phytoestrogens. These estrogens can be derivatized or modified to form, for example, conjugated equine estrogens, esterified estrogens, ethinyl estradiol, etc. Examples of esterified estrogens include, but are not limited to: estradiol-3,17-diacetate, estradiol-3-acetate, estradiol-17-acetate, estradiol-3,17-divalerate, estradiol-3-valerate, estradiol-17- valerate. Also included are selective estrogen receptor modulators (SERMS), for example, raloxifene, available under the trade name Evista® from Eli Lilly, and the like. Estrogens may also be present in the form of salts (for example, as sodium estrogen sulfate), isomers or prodrugs.

Phytoestrogens, which are plant-derived estrogens, are also included. Isoflavones are one of the main forms of phytoestrogens and have a common diphenol structure, which is similar to the structure of strong synthetic estrogens such as diethylstilbestrol and hexestrol. The main isoflavones found in humans include, but are not limited to, genistein, diadzein and equol.

“Oral estrogens” means any estrogen that is in a dosage form suitable for oral administration. Conjugated equine estrogens, esterified estrogens, and micronized estradiol are examples of oral estrogens. Commercially available oral estrogen products include conjugated equine estrogens, available under the trade name Premarin® from Wyeth-Ayerst Laboratories, esterified estrogens, available under the trade name Estratab® from Solvay Pharmaceuticals, and micronized 17β-estradiol, available under the trade name Estrase® Bristol Meyers Squibb.

“Progestin”, or “progesterone”, means any substance, natural or synthetic, that exhibits a biological or pharmacological effect primarily through binding to progestin receptors. Examples include, but are not limited to: progesterone, medroxyprogesterone acetate, norethindrone and norethindrone acetate, their esters, derivatives, prodrugs and isomers. Progestin can be administered to a woman to achieve several effects. Examples, without limitation, include ensuring endometrial safety during concomitant administration of estrogen and providing effective contraception. Although the amount of progestin required to achieve such effects may vary from woman to woman, methods for determining suitable and effective amounts of progestin to achieve the described goal or effect are well known to those of ordinary skill in the art.

“Sex hormone binding globulin”, or “SHBG”, also known as sex hormone binding protein (SHBP) and testosterone-estradiol binding globulin (TeBG), refers to whey protein that binds various sex hormones with high affinity (see table 1; from Dunn et al., Transport of Steroid Hormones: Binding of 21 Endogenous Steroides to Both Testosterone-Binding Globulin and Corticosteroid-Binding Globulin in Human Plasma, J. Clinical Endocrinology and Metabolism, Vol. 53: 58-67 (1981)). The reported binding affinity constants (K-values) for specific sex hormones and SHBG are shown in Table 1 as follows (borrowed from Dunn et al., 1981).

For the purposes of this application, SHBG binding affinity constants in excess of approximately 1 × 10 ⁶ liter / mol indicate a high binding affinity.

The structure and intended functions of SHBG have been described and characterized. See, e.g., Rosner et al., Sex Hormone-Binding Globulin Mediates Sreroid Hormone Signal Transduction at the Plasma Membrane, J. Steroid Biochem. Mol. Biol. Vol. 69: 481-5 (1999); Petra, P.H. The plasma Sex Steroid Binding Protein (SBP or SHBG). A Critical Review of Recent Developments on the Structure, Molecular Biology and Function, J. Steroid Biochem. Mol. Biol. Vol. 40: 735-53 (1991). Various methods have been used to quantify SHBG concentrations, including ammonium sulfate precipitation, gel filtration, equilibrium dialysis, dextran-coated charcoal, and radioimmunoassay. See, for example, Khan et al., Radioimmunoassay for Human Testosterone-Estradiol-Binding Globulin, J. Clinical Endocrinology and Metabolism. Vol. 54: 705-710 (1982). Using validated monoclonal immuno-radiometric analysis (Endocrine Sciences, Calabassas Hills, CA), it was found that the average serum SHBG level in healthy premenopausal women is 84 nmol / L and the normal range is 36-185 nmol / L. Serum levels of SHBG are known to increase in women who have been given oral, estrogen, estrogen-containing oral contraceptives, clomiphene, tamoxifen, raloxifene, phenytoin and sodium valproate, as well as in women who are pregnant, hyperthyroid, have chronic liver disease and HIV . See, for example, Bond et al., Sex Hormone Binding Globulin in Clinical Perspective, Acta. Obstet Gynecol. Scand. Vol. 66: 255-262 (1987); Miller et al., Transdermal Testosterone Administration in Women with Acquired Immunodeficiency Syndrome Wasting: A Pilot Study, J. of Clinical Endocrinology and Metabolism. Vol. 83: 2717-2725 (1998).

“Introduction” means a method by which a drug is provided to a subject. Administration can be accomplished in various ways well known in the art, such as oral and non-oral methods.

“Oral administration” can be achieved by swallowing, chewing, or sucking an oral dosage form containing the drug. “Non-oral administration” means any route of administration in which the pharmaceutical composition is not provided in a solid or liquid oral dosage form, wherein such a solid or liquid oral dosage form is conventionally intended to release and / or deliver a drug mainly in the gastrointestinal tract outside the oral cavity and / or buccal pocket. Such solid dosage forms include conventional tablets, capsules, droplets, etc. that do not substantially release a drug in the mouth or in the oral cavity.

It is understood that many oral liquid dosage forms, such as solutions, suspensions, emulsions, etc., and some oral solid dosage forms, can release some of the drug in the mouth or oral cavity when these formulations are swallowed. However, due to their very short transit time when passing through the mouth or oral cavity, the release of the drug from these formulations in the mouth or oral cavity is considered minimal or insignificant. Thus, buccal patches, adhesive films, sublingual tablets and lozenges that are intended to release the drug in the mouth are non-oral compositions for these purposes.

Thus, the term “non-oral” includes parenteral, topical, inhaled, implanted, ophthalmic, nasal and vaginal or rectal compositions and administrations. Further, implantable compositions should be included in the term “non-oral,” regardless of the physical location of the implant.

“Parenteral” administration can be achieved by injection of the drug composition intravenously, intraarterially, intramuscularly, intrathecal or subcutaneous, etc.

“Local (local) composition” means a composition in which the drug can be placed for direct application to the surface of the skin and from which an effective amount of the drug is released. Examples of topical formulations (i.e., topical formulations) include, but are not limited to, ointments, creams, gels, transdermal patches, sprays, vaginal rings and pastes. “Transdermal” (transdermal) means a route of administration that facilitates the transfer of a drug through the surface of the skin, in which the transdermal composition is applied to the surface of the skin.

Transdermal administration can be performed by applying, spreading, rolling, attaching, pouring, pressing, rubbing, etc. transdermal preparation on the surface of the skin. These and other routes of administration are well known in the art.

“Transdermal delivery system”, “transdermal patches” or simply “patches” refers to a device for delivering a type of matrix or fluid reservoir that is used for transdermal (transdermal) delivery of certain doses of a substance over a specific application period.

One example of a transdermal patch for administering an androgenic steroid in accordance with this invention is a matrix-type patch which contains a hermetic lining that is impermeable to androgenic steroids and defines the front or top surface of the patch and a solid or semi-solid matrix layer consisting of a homogeneous hormone mixture, a pressure sensitive polymer adhesive (sticky) carrier and optional one or more skin penetration enhancers. Matrix patches are known in the field of transdermal drug delivery. Examples, without limitation, having an adhesive matrix of transdermal patches are patches described or cited in US Patent Nos. 5122383 and 5460820, which are hereby incorporated by reference in their entirety.

Another example of a transdermal patch for administering an androgenic steroid in accordance with this invention is a patch of the type with a fluid reservoir system (LRS) that contains androgen and other optional ingredients, such as a penetration enhancer, in a carrier vehicle. The carrier excipient contains a liquid of the desired viscosity, such as a gel or ointment, which is prepared for enclosing in a reservoir having an impermeable liner and a permeable membrane for contacting the skin, or a membrane adhesive laminate providing diffusion contact between the contents of the reservoir and the skin. For use, a release liner is removed and the patch is attached to the skin surface. LRS patches are known in the field of transdermal drug delivery. Non-limiting examples of LRS transdermal patches are patches described or cited in US Patent Nos. 4,849,224, 4,983,395, which are hereby incorporated by reference in their entirety.

The terms “skin”, “skin surface”, “dermis”, “epidermis” and similar terms are used interchangeably herein and refer not only to the outer skin of a subject containing the epidermis, but also to the surfaces of mucous membranes onto which the drug composition can be administered. Examples of mucosal surfaces include respiratory (including nasal and pulmonary), oral (mouth and buccal surfaces in the mouth), vaginal, introital (surface of openings (entrances to the canal or hollow organ, such as the vagina)), labial and rectal surface. Thus, the term “transdermal” also includes “transmucosal”.

“Co-administration” (“co-administration”) and similar terms mean the administration of multiple substances to one individual, simultaneously or sequentially. So, when referring to estrogen and androgen, this term includes any situation in which women take oral estrogen and non-oral androgen. This term does not imply that estrogen and androgen should be administered at the same time. Rather, as long as a woman receives oral estrogen, the administration of non-oral androgen will fall within the definition of “co-administration.” It should be understood that estrogen and androgen should not be provided as a single product or through an identical route for “co-administration.”

The terms “finished form” or “composition” are used interchangeably herein. The terms “pharmaceutical substance” and “drug” are also used interchangeably to mean a pharmaceutically active substance or composition. These terms of the art are well known in the pharmaceutical and medical fields.

“Total serum levels”, “total blood levels” and “endogenous serum levels” refer to total serum levels of androgen or estrogen, including both protein bound and free androgen or estrogen. Some proteins, such as albumin, bind androgen or estrogen with low affinity, so that these sex hormones are functional (bioavailable) (i.e., exhibit their known or suspected effect). In contrast, some proteins, such as SHBG, bind androgen or estrogen with high affinity, making them non-functional. One skilled in the art knows how to measure and characterize these types of binding. See, for example, Dunn et al.

Thus, the term “total serum testosterone level” refers to the sum of: (1) free testosterone; (2) testosterone, which is weakly bound to serum proteins, such as albumin-bound testosterone; and (3) testosterone, which is strongly bound to high affinity whey proteins, such as SHBG-linked testosterone.

The term “protein-bound” includes all types of protein binding.

Total serum testosterone can be measured by known assay methods, such as radioimmunoassay (RIA). See, for example, the RIA procedure used by Endocrine Sciences, Inc. (Calabassas Hills, CA). This procedure is based on a RIA published by Furuyama et al., Radioimmunoassay for Plasma Testosterone, Steroids, 1970; 16: 415-428. Using this assay method, the normal range of total serum testosterone levels measured in healthy premenopausal women according to Endocrine Sciences, Inc. was reported to be 14-54.3 ng / dl (Miller et al., 1998).

“Endogenous free testosterone level,” or “physiological free testosterone level,” will refer to the level of free testosterone (FT) that is commonly found in adult women without symptoms associated with testosterone deficiency and / or excess testosterone and / or symptoms of unbalanced estrogen / androgen.

“Bioavailable”, “serum bioavailable” and similar terms refer to an androgen or estrogen that is not associated with SHBG. Thus, androgen, which is “free” (unbound) or “loosely bound” to serum albumin (easily dissociated from it) is considered bioavailable to tissues. Due to the high binding capacity (unsaturation) of albumin for testosterone, the serum concentration of albumin-bound testosterone will usually be proportional to the concentration of free testosterone. The proportionality coefficient corresponds to the product of the binding constant albumin-testosterone (3.6 × 10 ⁴ l / mol) and the concentration of serum albumin (expressed in mol / l). See Vermeulen et al., A Critical Evaluation of Simple Methods for the Estimation of Free Testosterone in Serum, J. of Clinical Endocrinology and Metabolism. Vol. 84: 3666-3672 (1999). Since the concentration of serum albumin is maintained within a relatively narrow range (for example, 4-5 g / dl; 5.8 × 10 ^-4 7.6 × 10 ^-4 mol / l), the proportionality coefficient is approximately 22. As a consequence of this dependence, the concentration of bioavailable testosterone can be approximately 23 times higher than the concentration of free testosterone, regardless of the concentrations of total testosterone and SHBG.

The concentration of bioavailable testosterone is usually measured using an ammonium sulfate precipitation method. See, for example, Nankin et al. Daytime Titers of Testosterone, LH, Estrone, Estradiol and Testosterone-Binding Protein: Acute Effects of LH and LH-Releasing Hormone in Men, J. Clinical Endocrinology Metabolism. Vol. 41: 271-81 (1975). Using this method, the normal range of bioavailable testosterone levels measured in healthy premenopausal women according to Endocrine Sciences, Inc. was reported to be 1.6-12.7 ng / dl or approximately 2-13 ng / dl.

“Free,” “unbound,” or similar terms refer to an androgen or estrogen that is not attached to any protein, such as SHBG or albumin. Thus, an androgen or estrogen that is not bound to a protein is considered “free.”

By way of non-limiting example, terms such as “free testosterone”, “unbound testosterone”, “free serum testosterone” refer to testosterone in serum that is not bound to a protein. Serum free testosterone levels can be measured by various laboratory methods, including equilibrium dialysis, ultrafiltration, a similar RIA method, and calculation from total testosterone, SHBG, and albumin levels. See, for example, Winters et al. The Analog Free Testosterone Assay: Are the Results in Men Clinically Useful? Clinical Chemistry. Vol. 44: 2178-2182 (1998); see also Vermeulen et al. (1999). It is believed that currently the equilibrium dialysis method provides the most accurate results. See Mathor et al., Free Plasma Testosterone Levels During the Normal Menstrual Cycle, J. Endocrinol. Invest. Vol. 8: 437-41 (1985). Using this method, it was reported that the normal range of free testosterone levels measured in healthy premenopausal women according to Endocrine Sciences, Inc. was 1.3-6.8 pg / ml, or about 2-7 pg / ml.

The term “woman” means a female person who benefits from adding androgen or estrogen in any way. In one aspect, a woman may be menopausal due to age, oophorectomy, or ovarian failure. In another aspect, the woman may receive oral estrogens for beneficial effects, for example, to prevent or delay bone mass reassignment (osteoporosis), to prevent or delay changes in blood lipids that would otherwise predispose the woman to cardiovascular disease. In another embodiment, this woman may show a deficiency or imbalance of estrogen and androgen hormones. In yet another embodiment, this woman may take oral estrogens for contraception.

“Improving health” means reducing, improving, or preventing the occurrence and / or intensity of symptoms associated with deficiency of androgenic steroids. Examples of such symptoms include, but are not limited to: sexual dysfunction, which can occur in the loss of sexual desire, decreased sensitivity to sexual stimulation, decreased irritability and ability to orgasm, lowered vitality, lowered mood, decreased sense of well-being, increased shyness, loss of muscle mass and function, poor body composition, i.e. the ratio of lean muscle mass to fatty muscles, pubic hair thinning and loss, urinary tract atrophy, dry and brittle hair of the scalp (scalp), dry skin, decreased cognitive abilities, dry eyes, autoimmune phenomena and their combination.

Increases and decreases in the presence and severity of such symptoms can be determined using various devices known in the art to evaluate each specific symptom. For example, sexual function in women can be assessed using self-assessment questionnaires, such as the Brief Index of Sexual Functioning for Women, (Taylor et al., 1994); Derogatis Interview for Sexual Functioning, Derogatis, L., The Derogatis Interview for Sexual Functioning (DISF / DISF-SR): an introductory report, J. Sex. Marital Ther. Winter 23 (4): 291-304 (1997) and other questionnaires such as Derogatis et al., Psychological assessment measures of human sexual functioning in clinical Trials, Int. J. Impot. Res., May 10 Suppl. 2: S13-20 (1998); as well as using research methods for blood supply to the genitals (Laan, 1998). Muscle mass, body composition, and bone mineral density are usually measured using dual energy x-ray absorptiometry (DEXA). Mood, well-being, and neurocognitive function can be measured using the Beck Depression Inventory (Beck et al., 1961), the psychological overall well-being index (Dupuy, 1984), and a battery of neurocognitive function tests. Dry eye syndrome can be evaluated using tests for the function of tearing, such as osmolality, volume, flow rate, Schirmer test, using artificial tear preparations and subjective questionnaires. See, for example, Mathers et al. Menopause and Tear Function: The Influence of Prolactin and Sex Hormones on Human Tear Production, Cornea. Vol. 17: 353-8 (1998). Immune function can be assessed by titers of circulating autoantibodies, by the number of CD4 + and CD8 + lymphocytes, and by the symptomatology of specific autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, etc.

“Increased,” as used in connection with SHBG levels, means the serum concentration of SHBG measured in a particular woman, which is higher than the average value for a healthy premenopausal woman reported by the clinical laboratory in which the SHBG level is measured. For example, the value obtained using the methodology of immunoradiometric analysis of Endocrine Sciences, Inc., would be considered as increased if it was more than 84 nmol / L. A “substantially elevated" level of SHBG refers to the concentration of SHBG in serum in a particular woman that is greater than the upper limit of the normal range for a healthy premenopausal woman reported by the clinical laboratory in which this level of SHBG is measured. For example, the value obtained using the methodology of immunoradiometric analysis of Endocrine Sciences, Inc., would be considered as significantly increased if it was more than 185 nmol / L. Due to the different methods used to measure SHBG in different laboratories of clinical standards, and the corresponding variations in the average values and normal ranges reported by them, the definitions of increased SHBG values given above apply to any validated method with correctly defined normal ranges.

“Effective amount” means the amount of a substance that is sufficient to achieve its intended purpose or its intended effect. Various biological factors can affect the ability of a delivered substance to fulfill its intended purpose. Thus, an “effective amount” may depend on such biological factors. By way of example, without limitation, a woman having a serum SHBG level of 225 nmol / L may need a higher dose of testosterone to achieve the intended effect than a woman having a serum testosterone level of 100 nmol / L. Thus, although the doses of testosterone in such women will vary, each dose should be considered as an “effective amount” until it achieves the desired effect. The definition of “effective amount” is well within the ordinary skill in the art.

Numerous evaluations can be used to measure the achievement of the desired effects in the case of delivery of androgens and estrogens, which are well known in the art. Such evaluations may be performed by a doctor or other qualified medical personnel and may include physical examinations, blood tests, etc.

“Therapeutic effect” means the desired result, which is achieved to some extent. In the context of the addition of androgens and estrogens presented in this patent application, a number of desired results are called “improving health”. In one aspect, therapeutic effects can be achieved by delivering an “effective amount” of a substance that can produce the desired result to a selected degree. Although the achievement of therapeutic effects can be measured by a physician or other qualified medical personnel using estimates known in the art, it is understood that individual variation and response to treatment can make achieving therapeutic effects a subjective decision.

Concentrations, amounts, solubility and other digital data can be presented here in the format of ranges. It should be understood that such a format of ranges is used only for convenience and brevity and should be interpreted flexibly to include not only digital values precisely indicated as range boundaries, but also include all individual digital values or subranges enclosed in a given range as if each numerical value and each subrange were precisely named.

For example, a concentration range of 0.5-15 pg / ml should be interpreted as including not only the precisely defined concentration limits of 0.5 pg / ml and 15 pg / ml, but also including individual concentrations in this range, such as 0, 5 pg / ml, 0.7 pg / ml, 1.0 pg / ml, 5.2 pg / ml, 11.6 pg / ml, 14.2 pg / ml, and sub-ranges such as 0.5-2 5 pg / ml, 4.8-7.2 pg / ml, 6-14.9 pg / ml, etc. This interpretation should be applied regardless of the width of the range or the characteristics described.

B. Invention

A recent study showed that androgens and, in particular, testosterone contribute significantly to the health and well-being of women. In one aspect, Ebert et al. US Pat. No. 5,460,820 describes a composition and method for administering testosterone transdermally using a patch as a delivery system. These compositions and methods maintain total serum testosterone levels in the “physiological range” between about 15 and 80 ng / dl with transdermal administration of about 50-500 μg / day of testosterone from the testosterone matrix. It is believed that non-oral delivery of androgens is safer for the liver and provides longer delivery than oral methods, since the effects of first-pass metabolism are avoided. Oral delivery of estrogen, on the other hand, makes possible an improved serum lipid profile. However, it has been found that the above general serum testosterone levels for women may not be an accurate indicator of therapeutically effective testosterone levels in women with elevated or substantially elevated levels of SHBG, for example, in women receiving oral estrogens.

Binding of testosterone to SHBG is known to reduce testosterone transport to androgen-sensitive tissues, for example, tissues expressing androgen receptors. It is also known that such binding decreases the metabolic clearance rate of testosterone in both men and women. See, for example, Vermeulen et al. Metabolic Clearance Rate and Interconversion of Androgens and the Influence of the Free Androgen Fraction, J. Clinical Endocrinology and Metabolism. Vol. 48: 320-326 (1979); Longcope et al. Free Estradiol, Free Testosterone and Sex Hormone-Binding Globulin in Perimenopausal Women, J. Clinical Endocrinology and Metabolism. Vol. 64: 513-518 (1987). Due to the effect of SHBG levels on testosterone binding and clearance, the serum levels of total, free and bioavailable androgen, which are achieved by the administration of androgen to a particular individual, will depend on the individual's SHBG level. However, the effect of SHBG levels on serum androgen levels obtained cannot be accurately predicted based on current knowledge, and experimental data are needed.

To provide such data, pharmacokinetic studies were performed in three groups of surgically menopausal women (i.e., women in menopause due to surgery), who were injected with 300 μg / day of testosterone in the form of a transdermal patch with a testosterone-containing matrix twice a week for 7 days. One group did not receive estrogen replacement therapy (ERT) for at least one month, the second group received transdermally estradiol (E2) at a dose of 0.1 mg / day, and the third group received oral conjugated equine estrogens (CEE) at a dose of 1, 25 mg / day. Measurements of the level of SHBG obtained before application of the patch, and the levels of total and free testosterone obtained before and during the second 3.5-day period of application of the patch, were performed by Endocrine Sciences. The obtained hormone data (mean ± SEM (standard error of the mean)) for these three groups of surgically menopausal women participating in this clinical trial are summarized in table 2 below.

It should be noted that the normal range for SHBG levels is 36-185 nmol / L when using the Endocrine Sciences assay. Further, changes in levels of total testosterone and free testosterone are time-average changes from changes from baseline levels during a 3.5-day patch application.

As shown in table 2, the average level of SHBG in the group with oral estrogen was approximately 2.5 times greater than in other groups, and exceeded the upper limit of the normal range. SHBG levels in the transdermal estrogen group were comparable to women who did not receive estrogen replacement therapy (ERT). The average increase in total testosterone levels during application of the patch, i.e. the time-averaged change from baseline was approximately 30% higher in the oral estrogen group compared to the other two groups.

In contrast, the average increase in free serum testosterone in the oral estrogen group was about 40% lower than in the other two groups. These results show that by lowering testosterone clearance, elevated SHBG levels lead to an increase in the total serum testosterone levels obtained during transdermal testosterone administration. However, despite an increase in total serum levels, free serum testosterone levels and, as a result, bioavailable serum testosterone levels are reduced by elevated SHBG levels, presumably due to increased SHBG testosterone binding. These discoveries are new and unexpected and could not be predicted from earlier studies.

To further illustrate these new SHBG actions on testosterone levels, individual increments of total serum testosterone and free serum testosterone obtained during transdermal administration of 300 μg / day testosterone to surgically menopausal women receiving transdermal or oral estrogen were plotted against individual SHBG levels on figure 1 and 2, respectively. As shown on logarithmic scales, increments in total serum testosterone become large with increasing levels of SHBG, while increments in free testosterone become smaller with increasing levels of SHBG.

To further illustrate the new and unexpected effect of elevated SHBG levels on non-oral administration of testosterone, Table 3 below provides estimates of the testosterone delivery rate necessary to achieve a specific increase in free testosterone (FT), which were obtained as a function of SHBG level using a power-type regression equation given figure 2. As shown in Table 3, the required delivery rate to achieve a specific increase (change) in FT increases markedly as SHBG levels increase. For example, the delivery rate required to achieve an increase of 15 pg / ml in a patient whose SHBG level is 700 nmol / L is estimated to be 2484 μg / day, and this value is substantially greater than the value described in the prior art.

For the delivery rates given above, changes in the overall testosterone level (ng / dl) corresponding to the desired change in free testosterone level and a specific SHBG level can be predicted using the power-type regression equation shown in FIG. 1. Table 4 below provides an illustration of such predictions. As shown in table 4, changes in the level of total testosterone, corresponding to a specific change in the level of free testosterone, increase markedly with increasing levels of SHBG. For example, in a case corresponding to a change in free testosterone of 15 pg / ml in a patient whose SHBG level is 700 nmol / L (i.e., a delivery rate of 2484 μg / day), the predicted increase in total testosterone is 820 ng / dl.

It should be understood that when extrapolating the results and predictions of Tables 2, 3 and 4 relative to the actual patient, the baseline testosterone level of the patient (i.e. the level of total or free testosterone before treatment) should be added to the expected change in testosterone level due to treatment. For individuals with baseline levels that are subnormal, the final hormone levels resulting from the treatment will be close to the change itself.

The above new findings and predictions indicate that the administration of androgens to women taking oral estrogens, or women who usually have elevated levels of SHBG, will give levels of free and / or bioavailable testosterone, which will be significantly lower compared to women who take non-oral estrogens or that have low or normal levels of SHBG. In addition, women on oral estrogen therapy or women with elevated levels of SHBG will need doses of androgens that may exceed doses previously considered optimal in women with normal levels of SHBG. In addition, administration of such doses will produce levels of total serum testosterone in excess of the generally recognized normal ranges. It should also be noted that for some therapeutic applications, such as short-term androgen applications, the desired therapeutic levels of free and / or bioavailable testosterone could also be higher than the corresponding normal physiological ranges. Thus, the present invention provides methods, compositions, and kits for administering an androgenic steroid to improve a woman's health under conditions where the woman's SHBG levels are elevated.

C. Various aspects

In one aspect, the invention provides a method and kit for administering sex hormones, such as androgens and estrogens, to women. In another aspect, the invention provides a method and kit for non-oral administration of androgenic steroids to a woman having elevated levels of SHBG, for alleviating the symptoms associated with androgen hormone deficiency. In yet another aspect, the invention provides a method and kit for non-oral administration of androgenic steroids to a woman who receives oral estrogen supplementation. In a further aspect, the invention provides a method and kit for co-administration (co-administration) of an orally administered estrogen and a non-oral administration of an androgenic steroid. It has been found that these methods and kits for administering estrogens and / or androgenic steroids are useful in improving health, sexual function and well-being.

In one aspect of the invention, androgen can be administered in a dose sufficient to achieve a therapeutic effect equivalent to a serum free testosterone level of from about 0.5 to about 30 pg / ml. In another aspect of the invention, androgen can be administered at a dose sufficient to achieve a therapeutic effect equivalent to a serum free testosterone level of from about 1 to about 15 pg / ml. In another aspect of the invention, androgen can be administered at a dose sufficient to achieve a therapeutic effect equivalent to a serum free testosterone level of from about 1.3 to about 6.8 pg / ml, or from about 2 to about 7 pg / ml. In yet another aspect of the invention, androgen can be administered in a dose sufficient to achieve a therapeutic effect equivalent to a serum free testosterone level of from about 3 to about 10 pg / ml.

In one aspect of the invention, androgen can be administered at a dose sufficient to achieve a therapeutic effect equivalent to a serum bioavailable testosterone level of from about 1 to about 70 ng / dl. In another aspect of the invention, androgen can be administered at a dose sufficient to achieve a therapeutic effect equivalent to a serum bioavailable testosterone level of from about 2 to about 35 ng / dl. In yet another aspect of the invention, androgen can be administered in a dose sufficient to achieve a therapeutic effect equivalent to a serum bioavailable testosterone level of from about 2 to about 13 ng / dl.

In one aspect of the invention, androgen can be administered at a dose sufficient to achieve a therapeutic effect equivalent to a serum total testosterone level of from about 15 to about 1000 ng / dl. In another aspect of the invention, androgen can be administered at a dose sufficient to achieve a therapeutic effect equivalent to a serum total testosterone level of from about 85 to about 1000 ng / dl. In a further aspect of the invention, androgen can be administered in a dose sufficient to achieve a therapeutic effect equivalent to a serum level of total testosterone of from about 100 to about 1000 ng / dl.

In one aspect of the invention, androgen can be administered at a dose sufficient to achieve a therapeutic effect equivalent to a dose of testosterone of at least about 50 μg / day. In another aspect of the invention, androgen can be administered at a dose sufficient to achieve a therapeutic effect equivalent to a testosterone dose of from about 75 to about 3000 μg / day. In a further aspect of the invention, androgen can be administered in a dose sufficient to achieve a therapeutic effect equivalent to a testosterone dose of from about 600 to about 3000 μg / day. In yet another aspect, androgen can be administered in a dose sufficient to achieve a therapeutic effect equivalent to a dose of testosterone from about 700 to about 3000 μg / day.

One of the non-oral delivery methods for a dose of androgen is topical administration. Compositions for topical administration may include skin penetration enhancer (s) to increase the level of androgen release into the skin. Examples, without limitation, of skin penetration enhancers that can be used are described or cited in US Pat. The penetration enhancer index is further described by David W. Osborne and Jill J. Henke in their Internet publication entitled Skin Penetration Enhancers Cited in the Technical Literature, which can be found at the web address (worldwide computer network address) known as pharmtech. com / technical / osborne / osborne.htm, which is hereby incorporated by reference. An effective amount of an enhancer may be included in a pharmaceutically acceptable carrier. Various carriers may be suitable depending on the type of delivery composition desired. By way of example, without limitation, if necessary, a transdermal patch with an adhesive matrix, the carrier may be adhesive. In another aspect, when a patch of a liquid reservoir system (LRS) is desired, the carrier may be a gel, cream, ointment, lotion, or other suitable formulation known in the art.

Transdermal patches for transdermal delivery of androgenic steroids can be made by conventional methods used in the field of transdermal drug delivery devices. For example, androgens, a carrier and enhancers can be mixed in the desired proportions to form a homogeneous mixture and incorporated into a transdermal device. Various methods are known in the art for the manufacture of various types of transdermal devices, such as adhesive matrix patches and patches with a fluid reservoir system (LRS).

In addition to transdermal testosterone patches, other non-oral androgen delivery systems include, but are not limited to: intramuscular injections of testosterone esters, subcutaneous implanted testosterone implants, and topical preparations of testosterone, methyltestosterone, and other androgens. Devices and methods for these non-oral applications are well known in the art.

The need for sex hormone replenishment, such as estrogen and androgenic steroids, should be determined by a doctor or other health care professional based on monitoring for signs and symptoms of sex hormone deficiency or based on the need for pharmacological intervention in conditions that are sensitive to hormone therapy. Not every woman will exhibit the same symptoms, and it may be that the levels of sex hormones may even be within the accepted physiological ranges, but, based on other factors, for example, on the basis of an increased level of SHBG, replenishment of sex hormones may still be necessary.

Symptoms of subfunctional androgen levels, including testosterone, may include, but are not limited to: sexual dysfunction, which may result in loss of sex drive, decreased sensitivity to sexual stimulation, decreased irritability, and ability to orgasm; reduced vital energy; depressed mood; decreased sense of well-being; increased shyness; loss of mass and muscle function; unfavorable body composition, i.e. the ratio of the mass of “lean” muscles to the mass of “fat” muscles; thinning and loss of pubic hair; genitourinary atrophy; dry and brittle hair of the scalp (scalp); dry skin decreased cognitive abilities; dry eyes autoimmune phenomena or their exacerbation and their combination.

Women who take oral estrogens can also benefit from androgen therapy, as it can reduce the soreness of the breast that can occur with estrogen. Due to the known antiproliferative effects on breast tissue, androgens can also reduce the risk of developing breast cancer associated with the use of estrogen. Thus, it is highly desirable, if not necessary, that the addition of testosterone for a female patient be based on the diagnosis of a doctor who prescribes the method of application, dose and duration of treatment.

When co-administered with androgenic steroids, estrogen, for example, conjugated equine estrogen, can be administered orally in a dose range between about 0.2 and 3.0 mg / day. This dose can be adjusted according to the individual needs of the woman and the activity of the administered estrogen. The dose of oral estrogen can be taken as a single daily dose or in the form of two or more smaller quantities. Ideally, for women who experience vasomotor symptoms, the lowest effective dose of estrogen is used to control vasomotor instability. Lower doses can be used for women who do not suffer from vasomotor symptoms, but who will benefit from other health benefits, such as cardiovascular and bone benefits. In the case of oral contraceptive use, ethinyl estradiol is usually given cyclically in a regimen of 21 days with ethinyl estradiol, 7 days with placebo.

In one aspect, the invention provides a method and kit for administering a progestin with androgen and estrogen. It is known that progestins are administered to women to protect against endometrial hyperplasia. Progestins are also indispensable active ingredients in many oral contraceptives. In accordance with one aspect of the present invention, progestins may be administered by any means known in the art, as appropriate for the individual. The amount of progestin that is effective in achieving the desired goal can vary from woman to woman. Methods for determining the effective amount of progestin, i.e. an amount sufficient to achieve the desired therapeutic effect is well known to those of ordinary skill in the art.

Based on the above doses and laboratory tests, one of skill in the art can easily determine how much specific androgenic steroid or testosterone derivative to administer to obtain the desired levels of androgenic steroid in serum that can be achieved using more than one androgenic steroid or one form of testosterone. It is important that the dose of an androgenic steroid or testosterone derivative is sufficient to benefit a female recipient without administering too high a dose. The introduction of appropriate dose levels to obtain the optimal risk / benefit ratio is well within the ordinary skill in the art.

In the variants contained in the following examples, a dose of approximately 50-3000 μg / day of an androgen steroid is administered to a woman taking oral estrogen in an estrogen replacement therapy (ERT) regimen or as a contraceptive. Doses in this range are sufficient to provide a therapeutic response. However, this dose, the most suitable for a particular woman, can be determined empirically (for example, by varying the delivered dose and evaluating the effects on libido, sexual function, mood, general feeling of well-being, etc.). Thus, due to the natural variability in hormone sensitivity, the exact dose is not as decisive as obtaining the achieved physiological response for a particular patient, which can correspond to a total serum testosterone level of from about 15 to about 400 ng / dl or a serum free testosterone level of from about 0.5 to about 15 pg / ml.

The following examples are intended only to illustrate various aspects of the invention described herein and are not intended to limit in any way the scope of the claimed invention. Other aspects of the invention that are considered equivalent from the point of view of those skilled in the art are also within the scope of this invention.

Example 1

In surgically menopausal women aged 20-55 years, oral estrogen and transdermal testosterone were administered as follows. Estrogen consisted of conjugated equine estrogen (Premarin® tablets) in a daily dose of 0.625-2.5 mg. Transdermal testosterone was administered using a transdermal patch having a matrix that was applied to the stomach twice a week and which had a delivery rate of 300 μg / day. The duration of co-administration (co-administration) was 12 weeks. After 12 weeks, this treatment regimen improved sexual function, mood, and a sense of well-being compared to the administration of conjugated equine estrogen alone.

It was found that serum hormone levels in this treatment regimen according to Endocrine Sciences (Calabassas Hills, Calif.) Were in the following ranges: total testosterone (15.5-254.3 ng / dl), free testosterone (1.7-33.7 pg / ml), bioavailable testosterone (2.3-71 ng / dl), estradiol (5-280 pg / ml) and estrone (8-410 pg / ml). The levels of sex hormone-binding globulin ranged from 62.7 to 563 nmol / L, and in 92% of cases they were elevated and in 48% of cases they were significantly elevated in accordance with the definitions of “elevated” and “substantially elevated” given here . It should be noted that 73% of women on the treatment regimen with oral estrogen and transdermal testosterone reached levels of total testosterone of more than 80 ng / dl, the upper limit of the normal range commonly recognized in this field. In contrast, 78% had a free testosterone level below 6.8 pg / ml (the upper limit of the normal range for Endocrine Sciences) and 97% had a free testosterone level below 15 pg / ml, which is within the therapeutically acceptable range considered here. Similarly, 68% of women had a bioavailable testosterone level below 12.7 ng / dl (the upper limit of the normal range for Endocrine Sciences) and 97% had a bioavailable testosterone level below 35 ng / dl, which is within the therapeutically acceptable range considered here.

Example 2

The combination of androgenic compounds and estrogenic compounds can be administered to women who are naturally menopausal, in accordance with the following treatment regimen.

Androgen: topical administration of testosterone in a suitable carrier excipient, such as a cream or ointment, which optionally contains a penetration enhancer necessary to achieve the desired serum testosterone levels. The androgen-containing cream may contain cetyl zfirs, cetyl alcohol, white wax, glyceryl monostearate, dusty glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin and mineral oil. Each gram of this cream contains approximately 400 mcg of testosterone. About 1 g of this cream is applied to the skin or stomach when going to bed. The achieved concentrations in serum of free testosterone can be in the range of 0.5-15 pg / ml, and the achieved concentrations of total testosterone can be in the range of 30-250 ng / dl.

A dose metering device may be used to control the amount of testosterone administered. Dose adjustments can be made either on the basis of symptom relief, for example, restored libido, or to achieve the desired serum free testosterone concentrations. Ranges for symptom relief may vary between 1-20 pg / ml serum free testosterone.

Estrogen Compound: Oral conjugated equine estrogen tablets may be given at an initial dose of 0.625 mg / day. If necessary, doses can be increased to 1.25 mg / day for better symptom control, or can be reduced to 0.3 mg / day when vasomotor symptoms subside to maintain benefits for serum bones and lipids.

In women who have an intact uterus, it is important that a sufficient amount of progesterone is present in the serum to exclude endometrial hyperplasia, which may be the result of non-resistance estrogen replacement therapy.

The benefits of a combined hormonal treatment regimen may be seen by the patient within the first 6 weeks of administration, but variable responses may occur. Hormones are usually administered over an extended period of time to maintain good health.

Example 3

The androgenic compound and estrogenic compound can be administered to women who are postmenopausal to relieve the signs and symptoms associated with fragility, such as loss of bone and muscle mass and function, decreased cognitive abilities and reduced energy.

Androgen: Intramuscular injection of 150 mg of testosterone enanthate once a month. Testosterone enanthate can be prepared in such a way that it contains 200 mg per ml in sesame oil. In order to provide 150 mg of testosterone enanthate, the injectable dose should be 0.75 ml.

Estrogen: oral estrogens are provided in the range of 0.3-3.0 mg / day.

The administration is performed until the benefits of the treatment are desired and considered useful according to the prescribing physician.

Example 4

Androgenic compounds and estrogenic compounds can be administered to women with premature ovarian failure, for example, women whose ovarian function is permanently suspended until the age of 40 years.

Androgen: methyltestosterone can be given via the buccal route at a dose of 1 mg / day to achieve an improvement in sexual function that is equally effective relative to the improvement produced by testosterone at serum levels of about 50-300 ng / dl. A buccal tablet may be a two-layer tablet consisting of a drug layer and a bioadhesive layer (50 mg each). The composition of the drug layer (in wt.%) Can be 2% methyltestosterone, 0.75% magnesium stearate, 0.1% FD&C yellow No. 6, 24% Klucel HXF and 73.15% mannitol. The composition of the bioadhesive layer (in wt.%) May be 69.25% polyethylene oxide, 30% carbomer 934P and 0.75% magnesium stearate. The adhesive side of the tablet is applied to the gum of the upper jaw, and the side with the drug is facing the buccal mucous membrane covering the gum. The drug is absorbed transmucosally (through the mucous membrane) as the tablet dissolves over time. The tablet can be used once a day after breakfast.

Estrogen: Estrace®, Bristol-Myers Squibb Co., an oral micronized (powdered) tablet product, may be administered at a dose of 2 mg / day to alleviate menopausal symptoms and prevent bone loss (osteoporosis).

In addition, progestin, such as medroxyprogesterone acetate, can be administered orally at a dose of 5 mg / day during the last ten days of each month to induce endometrial separation.

Although these examples are primarily aimed at delivering an androgenic steroid to ensure its replenishment, based on determining the need for this, this introduction should be carried out in conjunction with the oral administration of estrogen compositions.

Claims (31)

1. The use of an androgenic steroid for the preparation of a medicament which, when administered orally in an effective amount, improves the health of a woman who has an increased or substantially elevated level of sex hormone-binding globulin (SHBG). 2. The use according to claim 1, characterized in that said elevated level of SHBG is above about 84 nmol / L. 3. The use according to claim 1, characterized in that said substantially elevated level of SHBG is above about 185 nmol / L. 4. The use according to claim 1, characterized in that said substantially elevated level of SHBG is above about 300 nmol / L. 5. The use according to claim 1, characterized in that the woman receives an orally administered estrogen supplement. 6. The use according to claim 5, characterized in that the orally administered addition of estrogen is administered together with a non-oral administration of an androgenic steroid. 7. The use according to claim 5, characterized in that the orally administered estrogen is a member selected from the group consisting of 17β-estradiol, 17α-estradiol, conjugated equine estrogen, esterified estrogen, micronized estradiol, sodium estrogen sulfate, ethinyl estradiol, estrone , tibolone, a selective estrogen receptor modulator (SERM), phytoestrogen, their isomers and derivatives, and combinations thereof. 8. The use according to claim 5, characterized in that said estrogen is administered in a dose sufficient to achieve a therapeutic effect equivalent to a dose of conjugated equine estrogen from about 0.2 to about 3.0 mg / day. 9. The use according to claim 5, characterized in that the woman is additionally treated with progestin. 10. The use according to claim 9, characterized in that the amount of progestin is sufficient to ensure endometrial safety. 11. The use according to claim 9, characterized in that the amount of progestin is sufficient to ensure effective contraception. 12. The use according to claim 1, characterized in that the improvement in women's health is manifested by the restoration, strengthening or improvement of a characteristic selected from the group consisting of sexual desire, frequency of sexual activity, stimulation of the genital organs, ability to achieve orgasm, pleasure during sexual activity activity, increase in sexual activity, vital energy, feelings of well-being, mood and feelings of emotional health, shyness, cognitive abilities, muscle mass and function, body composition, mineral noy density of bones, skin and hair, pubic hair, atrophy of the urogenital tract, vaginal dryness, dry eyes, health in autoimmune conditions, vasomotor instability, breast tenderness, symptoms of premenstrual syndrome and combinations thereof. 13. The use according to claim 1, characterized in that said androgenic steroid is a member selected from the group consisting of testosterone, methyltestosterone, androstenedione, adrenosterone, dehydroepiandrosterone, oxymetholone, fluoxymesterone, methandrostenolone, testolactone, pregnenolone nestrolone, neronolone-nestro-nestro-olone-nestro-olone-nestro-olone-nestro-olone-nestro-olone-nestro-olone-nestrolone, 17α dihydrotestosterone, danazol, oxymetholone, androsterone, nandrolone, stanozolol, ethylestrenol, oxandrolone, bolasterone and mesterolone, testosterone propionate, testosterone cypionate, test phenyl acetate toosterone, testosterone enanthate, testosterone acetate, testosterone bicylate, testosterone heptanoate, testosterone decanoate, testosterone caprate, testosterone isocaprate, their isomers and derivatives, and combinations thereof. 14. The use according to claim 1, characterized in that said androgenic steroid is administered in a dose sufficient to achieve a therapeutic effect equivalent to a total serum testosterone level of from about 15 to about 1000 ng / dl. 15. The use of claim 14, wherein said dose of an androgenic steroid is sufficient to achieve a therapeutic effect equivalent to a total serum testosterone level of from about 85 to about 1000 ng / dl. 16. The use of claim 14, wherein said dose of an androgenic steroid is sufficient to achieve a therapeutic effect equivalent to a total serum testosterone level of from about 100 to about 1000 ng / dl. 17. The use according to claim 1, characterized in that said androgenic steroid is administered in a dose sufficient to achieve a therapeutic effect equivalent to a level of free serum testosterone from about 0.5 to about 30 pg / ml. 18. The use according to claim 17, wherein said dose of the adrogenic steroid is sufficient to achieve a therapeutic effect equivalent to a level of free testosterone in serum of from about 1 to about 15 pg / ml. 19. The use according to claim 17, wherein said dose of the adrogenic steroid is sufficient to achieve a therapeutic effect equivalent to a serum free testosterone level of from about 3 to about 10 pg / ml. 20. The use of claim 17, wherein said dose of an androgenic steroid is sufficient to achieve a therapeutic effect equivalent to a serum free testosterone level of from about 2 to about 13 pg / ml. 21. The use according to claim 1, characterized in that the said adrogenic steroid is administered in a dose sufficient to achieve a therapeutic effect equivalent to a level of bioavailable testosterone in serum from about 1 to about 70 ng / dl. 22. The use according to item 21, wherein the specified dose of androgenic steroid is sufficient to achieve a therapeutic effect equivalent to a level of bioavailable serum testosterone from about 2 to about 35 ng / dl. 23. The use according to item 21, wherein the specified dose of an adrogenic steroid is sufficient to achieve a therapeutic effect equivalent to a level of bioavailable serum testosterone from about 2 to about 13 ng / dl. 24. The use according to claim 1, characterized in that said androgenic steroid is administered in a dose sufficient to achieve a therapeutic effect equivalent to a dose of testosterone of at least about 50 μg / day. 25. The use according to paragraph 24, wherein said androgenic steroid is administered in a dose sufficient to achieve a therapeutic effect equivalent to a dose of testosterone from about 75 to about 3000 μg / day. 26. The use according to paragraph 24, wherein the specified androgenic steroid is administered in a dose sufficient to achieve a therapeutic effect equivalent to a dose of testosterone from about 600 to about 3000 μg / day. 27. The application of paragraph 24, wherein the specified androgenic steroid is administered in a dose sufficient to achieve a therapeutic effect equivalent to a dose of testosterone from about 700 to about 3000 μg / day. 28. The use according to claim 1, characterized in that said non-oral administration is a topical administration or parenteral administration, or a combination thereof. 29. The use of claim 28, wherein said parenteral administration is an intramuscular injection, or subcutaneous implantation, or a combination thereof. 30. The application of claim 28, wherein said local administration is a transdermal, transmucosal or sublingual administration, or a combination thereof. 31. A method of improving the health of a woman having elevated or substantially elevated levels of sex hormone-binding globulin (SHBG), comprising administering a medicament according to any one of claims 1-30.

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