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(12) Patent Application Publication (10) Pub. No.: US 2003/0027804 A1 Van Der Hoop (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2003/0027804 A1 Van Der Hoop (43) Pub US 2003OO27804A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0027804 A1 van der Hoop (43) Pub. Date: Feb. 6, 2003 (54) THERAPEUTIC COMBINATIONS FOR THE (57) ABSTRACT TREATMENT OF HORMONE DEFICIENCES The present invention relates to methods of treating, pre (76) Inventor: Roland Gerritsen van der Hoop, venting, or reducing the risk of developing a male or female Marietta, GA (US) menopause disorder or Symptom in a mammal by adminis tering to the mammal a SeX hormone binding globulin Correspondence Address: Synthesis inhibiting agent and one or more Steroids, includ Joseph A. Mahoney ing, for example, an androgen or an estrogen; to combina tions for treating, preventing or reducing the risk of devel Mayer, Brown & PlaTT oping a male or female menopause disorder or Symptom in P.O. Box 2828 a mammal, and to compositions for treating, preventing, or Chicago, IL 60690 (US) reducing the risk of developing a male or female menopause disorder or Symptom in a mammal, where the composition (21) Appl. No.: 09/892,981 comprises a SeX binding globulin Synthesis inhibiting agent and one or more Steroids, including, for example, an andro (22) Filed: Jun. 27, 2001 gen or an estrogen. In addition, the methods, combinations and compositions may be used in conjunction with other Publication Classification pharmaceutical agents aimed at improving Sexual perfor mance or impotence, increasing libido, or treating erectile (51) Int. Cl. .................................................. A61K 31/56 dysfunction, such as VIAGRACE), to enhance their effective (52) U.S. Cl. ............................................ 514/177; 514/178 CSS. US 2003/0027804 A1 Feb. 6, 2003 THERAPEUTIC COMBINATIONS FOR THE 0006 Testosterone, the major circulating androgen in TREATMENT OF HORMONE DEFICIENCES men, is Synthesized from cholesterol. The approximately 500 million Leydig cells in the testes secrete more than 95% FIELD OF THE INVENTION of the 6-7 mg of testosterone produced per day. In Women, 0001. The present invention relates to methods, combi the ovary and adrenals Synthesize Small amounts of test nations, and compositions for treating, preventing, or reduc osterone. Typically, testosterone is reduced at the 5 alpha ing the risk of developing an androgenic or estrogenic position into dihydrotestosterone, which Serves as the intra hormone deficiency in a male or female Subject, or for cellular mediator of most hormone actions. Although a treating, preventing, or reducing the risk of developing the variety of other naturally occurring androgens have been Symptoms associated with, or related to, an androgenic or identified, these are generally weak in potency; and it is now estrogenic deficiency in a male or female Subject. generally believed that they are androgens only to the extent that they can be converted in Vivo to testosterone and/or dihydrotestosterone. Two hormones produced by the pitu BACKGROUND OF THE INVENTION itary gland, luteinizing hormone (“LH) and follicle stimu 0002 Research into “male menopause” or “andropause” lating hormone (“FSH'), are required for the development shows that there is a drastic drop of serum levels of free and maintenance of testicular function and negatively regu testosterone of about 1.5% per year after puberty. While the late testosterone production. Circulating testosterone is total testosterone of a male does not drop drastically, the free metabolized to various 17-keto steroids through two differ testosterone, which is the biologically active part of the ent pathways. Testosterone can be metabolized to dihy testosterone, does drop precipitously with aging. In fact, a drotestosterone (“DHT”) by the enzyme 5C.-reductase or to Significant drop of free testosterone can occur as early as the estradiol (“E”) by an aromatase enzyme complex. early forties. Studies have shown that men with high test 0007. The gut metabolizes orally administered testoster osterone levels live longer, healthier lives and maintain one and the liver clears about 44% in the first pass. To Sexual potency. Studies have also shown that testosterone achieve clinically effective blood levels of testosterone, oral has the ability to Stop the spread of breast cancer in females. doses as high as 400 mg per day are required. The liver does Additionally, research has shown that testosterone has a not as extensively metabolize Synthetic androgens, Such as protective effect against autoimmune diseases. methyltestosterone and fluoxymesterone, and thus the Syn 0003. The female hormones, estrogen and progesterone, thetic androgens are more Suitable for oral administration. are known to drop drastically to very low levels after menopause. The American College of Physicians and the 0008. The major metabolites of androgens in urine are American College of Obstetricians and Gynecologists has physiologically inactive either as free Steroids or as water released position paperS Saying post-menopausal women Soluble conjugates. These metabolites are predominantly should Seriously consider preventive estrogen/progesterone etiocholanolone, a 5 alpha-reduced metabolite of testoster hormone replacement therapy for their benefit in reducing one; and androsterone, a metabolite of dihydrotestosterone. Osteoporosis and heart disease. Maintaining estrogen and It is now also recognized that testosterone (but not dihy progesterone levels has also been shown to improve a drotestosterone) can be aromatized into estradiol in a variety number of key risk factors for heart disease in post-meno of extraglandular tissues, a pathway that accounts for most pausal women. The benefits of estrogen/progesterone hor estrogen Synthesis in men and postmenopausal women. The mone replenishment therapy include prevention of role, if any, of the approximately 50 micrograms of estradiol Osteoporosis and heart disease, prevention of vaginal dry Synthesized each day in normal men has never been defined. neSS and thinning of the vaginal wall, relief from meno Nevertheless, the production of estradiol is considered a pausal Symptoms and hot flashes, and the possible benefit of normal phenomenon. Experimental evidence Suggests that reducing the onset of Alzheimer's disease, dementia, and estradiol affects the proliferation of male Sex Secondary cataracts. Studies have shown that when estrogen is replen organs, and that estradiol is necessary to induce prostate ished in conjunction with progesterone, the risks of uterine cancer in animal models. or breast cancer is nullified. 0009 Testosterone circulates in the blood 98% bound to 0004 A. Androgen Synthesis, Metabolism and Regula protein. In men, approximately 40% of the binding is to the tion high-affinity sex hormone binding globulin (“SHBG"). The remaining 60% is bound weakly to albumin. Thus, a number 0005 Androgens constitute a group of 19-carbon steroid of measurements for testosterone are available from clinical hormones that exert influence on the male genital tract and laboratories. The term “free’’ testosterone as used herein are involved with the development and maintenance of refers to the fraction of testosterone in the blood that is not Secondary male SeX characteristics Such as beard growth, bound to protein. The term “total testosterone” or “testoster deepening of the Voice at puberty, muscle and bone devel one' as used herein means the free testosterone plus protein opment, body Strength, and Sexual drive. Androgens are bound testosterone. The term “bioavailable testosterone” as Synthesized in the male testis, in the female ovary, and in the used herein refers to the non-SeX hormone binding globulin adrenal cortex of both sexes. Once released into the blood, bound testosterone and includes that weakly bound to albu these endogenous androgens Serve both as hormones and as min. Plasma concentrations of SeX hormone binding globu prohormones for the formation of two different classes of lin determine the ratio of free testosterone to bound test Steroids: 5 alpha-reduced androgens, which act as the intra osterone. Total Serum testosterone can be measured by cellular mediators of most actions of the male SeX hormones, assayS. Such as a radioimmunoassay, See, for example, and estrogens, which enhance Some androgenic effects and Furuyama et al., Radioimmunoassay for Plasma Testoster block others. one, Steroids, 16:415-428 (1970). US 2003/0027804 A1 Feb. 6, 2003 0010) The following table from the UCLA-Harbor Medi cal Center Summarizes the hormone concentrations in nor TABLE 2 mal adult men range: Mode of Application and Dosage of Various Testosterone Preparations TABLE 1. Preparation Route Of Application Full Substitution Dose In Clinical Use Hormone Levels in Normal Men Testosterone enanthate Intramuscular injection 200-25.0 g Hormone Normal Range every 2-3 weeks Testosterone cypionate Intramuscular injection 200 mg every 2 weeks Testosterone undecanoate Oral 2-4 capsules at 40 mg Testosterone 298 to 1043 ng/dL per day Free testosterone 3.5 to 17.9 mg/dL Transdermal testosterone Scrotal skin 1 membrane per day DHT 31 to 193 mg/dL patch Non-scrotal skin 1 or 2 systems per day DHTT Ratio O.O52 to O.33 Transdermal testosterone Implantation under the 3-6 implants of patch abdominal skin 200 mg every DHT - T 372 to 1349 ng/dL 6 months SHBG 10.8 to 46.6 mmol/L Testosterone implants FSH 1.0 to 6.9 mill J/mL. Under Development LH 1.0 to 8.1 ml/mL Testosterone cyclodextrin Sublingual 2.5-5.0 mg twice daily E. 17.1 to 46.1 pg/mL Testosterone undecanoate Intramuscular injection 1000 mg every 8-10 weeks Testosterone buciclate Intramuscular injection 1000 mg every 12-16 weeks Testosterone Intramuscular injection 315 mg for 11 weeks 0.011 The normal range for total serum testosterone lev microspheres els in healthy premenopausal women was reported to be 14 Obsolete to 53.3 ng/dL (Miller et al., Transdermal Testosterone 17C-Methyltestosterone Oral 25-5.0 g per day Administration in Women with Acquired Immunodeficiency Fluoxymesterone Sublingual 10–25 mg per day Syndrome Wasting. A Pilot Study, J. of Clinical Endocrinol Oral 10–20 mg per day ogy and Metabolism, Vol. 83(8): 2717-25 (1998)). Using an ammonium Sulfate precipitation method, the normal range of free testosterone levels in normal premenopausal women 0015 C.
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