Methods of treating androgen deficiency in men using selective a

Details Methods of treating androgen deficiency in men using selective a Methods of treating androgen deficiency in men using selective a

1997-06-13

1999-01-19

Jordan, Kimberly

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

514178, 514214, 514383, 514393, A61K 3156, A61K 3155, A61K 3141, A61K 31415

Patent

active

058613897

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP95/03733, filed Sep. 22, 1995.
The invention relates to the new use of aromatase inhibitors for the production of a pharmaceutical agent for treating a relative androgen deficiency in men.
In men, increasing age leads to a reduction of testicular androgen production and androgen concentration in the organism. In contrast to the situation in women, in whom estrogen production drops to castration values within a comparatively short period, this takes decades in men and involves an only gradual drop. It can nevertheless be clearly demonstrated that the total concentration of testosterone in the serum in the higher age group is significantly reduced compared to the values in young men. Because of the increase in steroid hormone-binding globulin (SHBG) that coincides with the ageing process, moreover, the proportion of free, unbound, and thus biologically active testosterone drops. In addition, it is clear that the serum levels of estrogens, although they are produced from androgens by direct conversion, do not drop in the same way as a function of age. As a result, the hormonal environment is significantly altered.
In men, the hormonal environment of the sexual steroids is characterized by a significant preponderance of androgens over estrogens. While the circulating main component of androgens, testosterone, is detected in the serum in units in the range of nmol/l, the estrogen antagonist, estradiol, can be measured only in the range of pmol/l. This considerable preponderance of androgen can be detected basically in the entire late puberty period of life, but there is a clearly different intensity of this androgen dominance as a function of age. With increasing age and particularly so in those over the age of 60, there is a less pronounced emphasis of the androgen preponderance. Table 1 shows published test series in which the ratio of testosterone serum to estradiol serum was determined in a comparison of young to old men (.gtoreq.60 years).


TABLE 1 ______________________________________ Comparison of the T/E.sub.2 Ratio in Serum in Young and Old Men Young (<60 Old (>60 % .DELTA. Reference years) years) (reduction) ______________________________________ Deslypere et 206:1 128:1 -38% al..sup.1) Pirke & Dorr.sup.2) 324:1 174:1 -46% Baker et al..sup.3) 372:1 225:1 -31% Murano et al..sup.4) a.m. 155:1 98:1 -37% p.m. 160:1 84:1 -48% ______________________________________ .sup.1) Deslypere, J. P. et al., Journal of Clinical Endocrinology and Metabolism, 64, No. 1, 1987 .sup.2) Pirke, K. M. & Doerr, P., Acta Endocrinologica, 74 (1973), 792-80 .sup.3) Baker, H. W. G. et al., Clinical Endocrinology, 5 (1976), 349-372 .sup.4) Murano, E. P. et al., Acta Endocrinologica, 99 (1982), 619-623
Although in the above-mentioned works, the ratio of testosterone to estradiol is indicated to some extent in considerably different orders of magnitudes--which can be attributed to the different measuring methods that are used--in older men there is clear agreement between the relative decreases in the preponderance of testosterone by 30-50% and the previous values found in young men.
The relative testosterone deficiency that occurs can have a disadvantageous effect in many respects. It is assumed that, e.g., an imbalance between androgens and estrogens that accompanies the drop in testosterone, generally at, for example, constant estrogen concentrations, is of decisive importance for the occurrence of benign prostatic hyperplasia (BPH). Regardless of the effects of estrogens, however, the relative testosterone deficiency per se can also be regarded as responsible for a number of age-related disorders. Reduction of muscle mass, accompanied by limitation of body performance capacity, reduction of bone density and in individual cases even osteoporosis, reduction of libido and potency, and psycho-vegetative disorders can be mentioned here. All above-mentioned Menopause!."
The standard treatment for this syndrome, which is presumably caused by androgen deficiency, has been

REFERENCES:
Herzog, Epilepsia, 32(Suppl. 6), pp. S34-S37, 1991.
deLignieres, Annals of Medicine, 25, pp. 235-241, Jun. 1993.
Matsumoto, Weston Journal of Medicine, 159(5), pp. 618-620, Nov. 1993
Bagatell, et al., Journal of Clinical Endocrinology and Metabolism, 78(3), pp. 711-716, Mar. 1994.
B. Lignieres, "Transdermal Dihydrotestosterone Treatment of `Andropause`," Ann Med, 25(3):235-41, Jun. 1993.
A. Matsumoto, "`Andropause`--Are Reduced Androgen Levels in Aging Men Physiologically Important?," WJM, 159(5), Nov. 1993.
C. Bagatell et al., "Effects of Endogenous Testosterone and Estradiol on Sexual Behavior in Normal Young Men," J. Clin. Endocrinology & Metabolism, 78(3):711-716, Mar. 1994.
A. Herzog, "Reproductive Endocrine Considerations and Hormonal Therapy for Men with Epilepsy," Epilepsia, 32(Suppl. 6):S34-S37, 1991.

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