Methods of treating androgen deficiency in men using selective aromatase inhibitors

Male menopause is characterized by significant decreases in serum levels of bioavailable androgens. The administration of aromatase inhibitors to men experiencing male menopause can remedy the relative androgen deficiency in men while at the same time approximating the physiological hormonal ratio of androgens to estrogens.

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 (&lt;60 Old (&gt;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 
disorders are often generically referred to as "Klimakterium virile Male 
Menopause!." 
The standard treatment for this syndrome, which is presumably caused by 
androgen deficiency, has been to supply androgens exogenically. Orally 
active androgens and long-chain testosterone esters with a depot effect 
that are to be administered intramuscularly are used. These forms of 
therapy are able to improve the symptoms caused by androgen deficiency, 
but produce an only inadequate approximation of the physiological state. 
As a substance to be administered orally, either a testosterone derivative, 
i.e., not a natural testosterone, is given (e.g., Proviron.RTM.), or the 
administration is accompanied by a disproportionately large increase in 
dihydrotestosterone (DHT) that deviates from the physiological situation 
(e.g., Andriol.RTM.). Unlike testosterone, DHT seems to be the androgen 
component that is of great importance for the development of BPH and also 
of androgenetic alopecia. 
In the case of depot formulations, the uneven release from the depot 
represents a problem that has not yet been satisfactorily resolved; it 
initially results in an increase of testosterone that extends 
significantly beyond the normal range, but toward the end of the dosage 
interval it leads to significantly reduced testosterone values. 
It has long been known that, in addition to androgens, estrogens are also 
involved in the endocrine control circuit that keeps the androgen level in 
men constant. By administering pharmacological doses of estrogen-active 
substances, such as, e.g., diethylstilbestrol, it is possible in patients 
with prostate cancer to largely suppress the hypophyseal LH release and to 
reduce the testosterone level in the serum to the castration level. 
From experience with use of pure antiandrogens in prostate-cancer patients 
who belong to the same age group as patients with male menopause, the 
extent of the counterregulatory potential can be assessed. If the central 
inhibiting action of androgens is suppressed by pure antiandrogens such as 
flutamide or casodex, in this age group this results in a 
counterregulatory increase in the serum testosterone concentration by 
about 50-60% compared to the starting value. In the case of treatment that 
lasts for months, however, there were indications of a lessening of the 
activity of counterregulation in the case of the prostate-cancer patients 
who were treated with pure antiandrogens, i.e., the initially 
significantly increased androgen levels drop again (Lund and Rasmussen, 
1988; Mahler and Denis, 1990: Delaere and Van Thillo, 1991). 
It is noteworthy that the reduction in androgens with age is not prevented 
by activation of the counterregulation mechanism. The reason for this is 
considered to be that, on the one hand, the testicular function generally 
diminishes with age, but, on the other hand, the feedback mechanism is 
also more sensitive to sexual steroids (Deslypere, J. P. et al., Journal 
of Clinical Endocrinology and Metabolism, 64, No. 1, 1987). Consequently, 
it has to be assumed that a less pronounced counterregulation is present 
in older men compared to younger men (see below), and thus for long-term 
use a serum androgen concentration that is higher than the starting value 
can be expected. 
In contrast, it is known that in younger men, in long-term treatment 
testosterone values are also effectively increased by daily treatment with 
antiestrogens (with considerable partial estrogenic action in each case) 
(Treatment of Male Infertility, Springer-Verlag Berlin, Heidelberg, New 
York 1982; Fuse, H. et al., Archives of Andrology 31 (1993) 139-145). 
Based on theoretical considerations, antiestrogens do not seem well suited 
for treatment of a relative androgen deficiency in men. Thus, treatment 
with antiestrogens has no effect on the estrogen level since the 
antiestrogens block the action of estrogens on their receptor. When 
antiestrogens are used as receptor blockers, inadequate compliance 
immediately led to an adverse effect since the higher estrogen 
concentration can act directly on the now free receptors because of the 
counterregulation that takes hold. 
Another drawback of antiestrogen treatment is the uncertainty as to whether 
the blocking of estrogen receptors in all estrogen-dependent tissues and 
organs is equally intense and what significance inherent estrogeneity, 
such as that of, e.g., the best known antiestrogen Tamoxifen, has for use 
in men. 
This invention has the object of providing suitable substances which remedy 
a relative androgen deficiency in men while at the same time approximating 
the physiological hormonal ratio of androgens to estrogens and which avoid 
the above-mentioned drawbacks. 
This object is achieved according to this invention by the use of at least 
one aromatase inhibitor for the production of a pharmaceutical agent for 
treating a relative androgen deficiency in men. 
It has been noted that the use of aromatase inhibitors in treating a 
relative androgen deficiency in older men results, surprisingly enough, in 
a long-term increase in the androgen level. 
By gradually lowering the estrogen concentration, a counterregulatory 
stimulation of androgen synthesis is induced. The aromatase inhibitors 
result in an endogenic rebalancing of the testosterone/estrogen ratio in 
men; as a result, the relative androgen deficiency is again compensated 
for. 
For the purposes of this invention, aromatase inhibitors are all those 
compounds that prevent estrogens from being formed from their metabolic 
precursors by inhibiting the enzyme aromatase (inhibition of 
biosynthesis). As aromatase inhibitors, therefore, all compounds are 
suitable that are suitable as substrates for aromatase, such as, for 
example, 
the testolactone (17a-oxa-D-homoandrost-1,4-diene-3,17-dione) that is 
described in the "Journal of Clinical Endocrinology and Metabolism," 49, 
672 (1979), 
the compounds androsta-4,6-diene-3,17-dione, 
androsta-4,6-dien-17.beta.-ol-3-one acetate, 
androsta-1,4,6-triene-3,17-dione, 4-androstene-19-chloro-3,17-dione, 
4-androstene-3,6,17-trione that are described in "Endocrinology" 1973, 
Vol. 92, No. 3, page 874, 
the 19-alkynylated steroids that are described in German Laid-Open 
Specification 31 24 780, 
the 10-(1,2,-propadienyl)-steroids that are described in German Laid-Open 
Specification 31 24 719, 
the 19-thio-androstane derivatives that are described in European patent 
application, publication no. 100 566, 
the 4-androsten-4-ol-3,17-dione and its esters that are described in 
"Endocrinology" 1977, Vol. 100, No. 6, page 1684 and U.S. Pat. No. 
4,235,893, 
the 1-methyl-15.alpha.-alkyl-androsta-1,4-diene-3,17-dione that is 
described in German Laid-Open Specification 35 39 244, 
the 10.beta.-alkinyl-4,9(11)-estradiene derivatives that are described in 
German Laid-Open Specification 36 44 358 and 
the 1,2.beta.-methylene-6-methylene-4-androstene-3,17-dione that is 
described in European Patent Application 0 250 262. 
According to this invention, selective aromatase inhibitors are preferably 
used for the production of a pharmaceutical agent for treating a relative 
androgen deficiency in men. Selective aromatase inhibitors are defined as 
those compounds that act as substrates for the aromatase and at the dosage 
used affect no enzyme other than aromatase in a clinically relevant way. 
Regarded as typical selective aromatase inhibitors according to this 
invention are, for example, the steroidal compounds 
1-Methyl-androsta-1,4-diene-3,17-dione (DE-A 33 22 285; atamestane), 
4-hydroxy-4-androstene-3,17-dione (formestane) as well as the non-steroidal 
aromatase inhibitors 
(RS)-5-(4-cyanophenyl)-5,6,7,8-tetrahydro-imidazo-(1,5.alpha.)-pyridine, 
hydrochloride (Cancer Res., 48, pp. 834-838, 1988; fadrozole), 
4-cyano-.alpha.-(1,2,4-triazol-1-yl)-benzyl!-benzonitrile (CGS 20267), 
5-cyclopentylidene-(1-imidazolyl)-methyl!-thiophene-2-carbonitrile (EP-A 0 
411 735; pentrozole), 
2,2'-5-(1H',2',4-triazol-1-yl-methyl)-1,3-phenylene!-bis(2'-methylpropioni 
trile) (arimidex) and 
(6-1-(4-chlorophenyl)-1,2,4-triazol-1-yl)-methyl!-1-methyl-1H-benzotriazol 
e, dihydrochloride (vorozole). 
The list of selective aromatase inhibitors above is not exhaustive; other 
compounds that are described in the above-mentioned materials and 
publications, as well as all other compounds that meet the set 
requirements, are also considered. 
Contrary to the assumption that the counterregulatory action could diminish 
in cases where older men are treated with an aromatase inhibitor over 
several months, data from longer-term studies, e.g., with atamestane on 
patients with BPH, show that even after treatment lasting 24 to 48 weeks, 
there is still a significant increase in testosterone concentration. 
Table 2 shows the corresponding results of a 24-week, four-way study in 
comparison to placebos (100 mg/d, 300 mg/d and 600 mg/d). 
TABLE 2 
______________________________________ 
Testosterone Serum Concentration (ng/ml) with 
atamestane 
.DELTA. % (median .+-. 
Daily Dose 
Previous Value 
After 24 Weeks 
SD) 
______________________________________ 
Placebo 4.13 4.18 6.00 .+-. 27.64 
100 mg 4.41 5.57 29.57 .+-. 34.70 
300 mg 4.50 6.15 40.88 .+-. 156.12 
600 mg 3.78 5.40 41.19 .+-. 37.62 
______________________________________ 
Tables 3 and 4 show the results after a 48-week treatment. 
TABLE 3 
______________________________________ 
Testosterone Serum Concentration (ng/ml) with 
Atamestane 
Previous 
Daily Dose 
Value After 48 Weeks 
.DELTA. % (X .+-. SD) 
______________________________________ 
Placebo 4.6 4.1 -0.1 .+-. 43.1 
400 mg 4.2 5.4 42.9 .+-. 53.5 
______________________________________ 
TABLE 4 
______________________________________ 
Testosterone Serum Concentration (ng/ml) with 
Atamestane 
Previous 
Daily Dose 
Value After 48 Weeks 
.DELTA. % (X .+-. SD) 
______________________________________ 
Placebo 4.6 4.6 2.8 .+-. 26.9 
100 mg 5.1 5.9 19.0 .+-. 36.8 
300 mg 4.7 6.6 41.7 .+-. 46.4 
______________________________________ 
Gradual lowering of the estrogen concentration induces a counterregulatory 
stimulation of androgen synthesis. To a certain extent, there is an 
endogenic testosterone substitution, by which the androgen/estrogen 
balance is again brought back to the "youthful" range. This substantiates 
the results of the longer-term treatment of older men (average age above 
60 years) with the selective aromatase inhibitor atamestane. 
In several clinical studies, atamestane was administered at varying dosages 
and over periods of up to 48 weeks to men in this age group to treat an 
existing BPH. The results show that with atamestane treatment for patient 
populations, there was a significant alteration of the 
testosterone/estradiol ratio in favor of testosterone. Table 5 provides 
the testosterone/estrogen ratio before and after the administration of 
atamestane for patient populations from 4 studies and 7 treatment groups. 
TABLE 5 
______________________________________ 
Changes in the T/E.sub.2 Ratio with Atamestane 
Treatment Previous Treatment 
Group Value (Time) % .DELTA. 
______________________________________ 
100 mg 248:1 418:1 +41% 
(48 weeks) 
300 mg 236:1 440:1 +46% 
(48 weeks) 
400 mg 207:1 454:1 +54% 
(48 weeks) 
200 mg t.i.d. 
116:1 214:1 +46% 
(8 weeks) 
100 mg 196:1 376:1 +48% 
(24 weeks) 
300 mg 199:1 473:1 +58% 
(24 weeks) 
600 mg 170:1 439:1 +61% 
(24 weeks) 
______________________________________ 
The administration of atamestane consistently results in a resetting of the 
testosterone/estradiol balance in favor of the androgenic component. This 
action was detectable over the entire observation period up to a maximum 
of 48 weeks of treatment. Although the peripheral estrogen reduction at 
daily doses of 100 mg-600 mg was equally intense, there was a trend toward 
greater emphasis of the androgenic proportion at high dosages. 
Assuming that the testosterone dominance that was reduced by 30-50% in the 
age group of patients over 60 years compared to the younger years 
(relative androgen deficiency) caused the symptoms of "male menopause," 
the goal is thus to restore the original "balance of power" between 
androgens and estrogens by administering a preferably selective aromatase 
inhibitor by stimulating endogenic testosterone substitution without the 
necessity of supplying hormones exogenically. Based on the understanding 
that the ratio prevailing in age is the result of a 30-50% reduction 
compared to the youthful values, i.e., is always 50-70% of the previous 
value, the corresponding "youthful" previous value can be calculated for 
each individual patient. A 70-year-old patient with a 
testosterone/estradiol ratio of 230:1 must accordingly be adjusted to a 
new balance in the range between 229:1 to 460:1, so that a preceding 30 or 
50% reduction is compensated for. Table 6 shows the result of such a 
calculation for the patient populations of the atamestane studies that are 
cited in Table 4. 
TABLE 6 
______________________________________ 
Comparison between Calculated "Youthful" T/E.sub.2 Range and 
Measured Values at Various Daily Atamestane Doses 
Calculated Target 
Value 
Previous Range to Compensate 
Achieved with 
Daily Dose 
Value for a 30-50% Reduction 
Atamestane 
______________________________________ 
100 mg 248:1 354:1 .fwdarw. 496:1 
418:1 
300 mg 236:1 337:1 .fwdarw. 472:1 
440:1 
400 mg 207:1 296:1 .fwdarw. 414:1 
454:1 
100 mg 196:1 280:1 .fwdarw. 392:1 
376:1 
300 mg 199:1 284:1 .fwdarw. 398:1 
473:1 
600 mg 170:1 243:1 .fwdarw. 340:1 
439:1 
______________________________________ 
At a daily dose of 100 mg, the target range is generally readily met. At 
higher dosages, however, the result is somewhat above the target range. 
Measuring the serum concentration of testosterone and estradiol can thus 
give early indication of whether the desired hormone balance was achieved 
and optionally whether dose adjustment can be undertaken. 
In general, 25 to 1000 mg, preferably 50 to 600 mg, of atamestane or a 
biologically equieffective amount of another aromatase inhibitor is used 
daily to treat a relative androgen deficiency in men. 
The aromatase inhibitors can be administered, e.g., orally or parenterally. 
For the preferred oral administration, suitable means are especially 
tablets, coated tablets, capsules, pills, suspensions, or solutions that 
can be produced in a way that is commonly used and familiar to one skilled 
in the art, with the additives and vehicles that are commonly used in 
galenicals for the formulation of aromatase inhibitors that are to be 
administered orally. 
The pharmaceutical agent that is produced according to the invention 
contains as an active ingredient per dosage unit the aromatase inhibitor 
atamestane at a dosage of 50 to 500 mg in addition to the commonly used 
additives, vehicles and/or diluents or other aromatase inhibitors at 
biologically equieffective dosages. 
A typical composition for a formulation of the aromatase inhibitor 
atamestane as a tablet is presented in the example below. 
EXAMPLE 
______________________________________ 
100.0 mg of 1-Methyl-androsta-1,4-diene-3,17-dione 
140.0 mg of lactose 
70.0 mg of corn starch 
2.5 mg of poly-N-vinylpyrrolidone 25 
2.0 mg of aerosil 
0.5 mg of magnesium stearate 
315.0 mg Total weight of the tablet, which is produced in 
the usual way on a tablet press. 
______________________________________ 
When aromatase inhibitors are used for treating male menopause, the 
estrogen concentration is effectively lowered. The easy controllability of 
the treatment distinguishes treatment with an aromatase inhibitor for 
stimulation of endogenic testosterone production from intervention with 
antiestrogens. As already explained, prospective control of the treatment 
by early measurement of pharmacodynamic parameters is not possible with 
antiestrogens.