Archives of Sexual Behavior, Vol. 8, No. 6, 1979
Effects of Testosterone Undecanoate on Sexual Potency and the Hypothalamic-Pituitary-Gonadal Axis of Impotent Males O. Benkert, 1 W. Witt, x W. Adam, 2 and A. Leitz 2
A double-blind comparison was made of the effects of testosterone undecanoate (TU) and placebo on sexual potency of 29 impotent men ages 45-75. The main criteria for inclusion in the study were a reduced or nonexistent capacity to have an erection during intercourse and no clinical signs of endocrinological pathology. All patients received placebo for 2 weeks. Then TU was given at a daily dose of 120 mg to 13 patients selected at random while the other patients continued to receive placebo. After 8 weeks all patients received placebo again for 2 weeks. An improvement in sexual potency was reported by five patients given TU and eight patients given placebo, with no significant differences between the groups. Treatment with TU influenced neither the hypothalamic-pituitary-gonadal axis, as judged by levels of prolactin, LH, FSH, and the LHRH-induced LH/FSH response, nor depression, anxiety, and somatic scores or performance tests. The only specific effect of TU treatment was to decrease the total plasma testosterone level. The present findings show pharmacotherapy with androgens to be no more effective than placebo in restoring sexual potency to sexually impotent men without androgen deficiency. Further studies may be needed to elucidate fully the effects of androgen administration on psychological and endocrinological variables in such patients. KEY WORDS: impotence; hypothalamic-pituitary-gonadal axis; testosterone undecanoate; androgen substitu~tion; sexual dysfunction; p sychoneuroendocrinology.
1 Psychiatric Clinic of the University of Munich, Nussbaumstrasse, 7, D-8000 M~nchen 2,
West Germany. 2 Andrologic Clinic of the University of Tiibingen, Tfibingen, West Germany. 471 0004-0002/79/1100-0471 $3.00/0 © 1979 Plenum Publishing Corporation
472
Benkert, Witt, Adam, and Leitz INTRODUCTION
Sexual impotence of some males is due to a deficiency of androgens, and administration of androgens to these men usually restores their potency (Neumann and Steinbeck, 1971). Sexual impotence can also occur in males without a demonstrable lack of androgens, and no pharmacotherapy has been shown to reliably restore their sexual potency (Benkert, 1979). Nevertheless, androgens are often prescribed to treat sexual impotence of males without signs of androgen deficiency. Since only a few pilot studies have been carried out to investigate effects of androgen therapy on non-androgen-dependent sexual impotence, the value of this treatment is uncertain. The present investigation was to determine on a large-scale, blind basis whether androgen treatment influences sexual impotenc e in males without clinical signs of androgen deficiency. Studies on the effects of androgen treatment on the hypothalamic,pituitary-gonadal axis and psychological functions of the men were performed as well.
PATIENTS AND METHODS The study was carried out on 36 males between ages 45 and 75 years old (mean age 56.5 years) who had sought treatment for sexual impotence, either at the Psychiatric Clinic of the University of Munich or at the Andrologic Clinic of the University of Tubingen. The main criteria for inclusion were a diagnosis of sexual impotence with reduced or nonexistent ability to have an erection during intercourse, a dysfunction persistent for at least 1 year, due to unknown etiology, and a prior history of normal penile erection (Benkert et al., 1975). Additional criteria for inclusion of men under 60 years old (17 in all) were (1) a regular female sexual partner, (2) at least one attempt at coitus per week, and (3) normal findings in an andrological examination including spermiogram of samples obtained by masturbation. All the men showed normal values in a neurological examination including EEG and X-ray of the skull and a clinical endocrinological examination (i.e., somatic examination and anamnesis), and none had psychosis or acute conflict with their sex partner at the time of the study. Each man gave his informed consent to participate in the study. The study lasted 20 weeks. During the first 2 weeks, all men received placebo (two capsules in the morning and one capsule in the evening) in a single-blind fashion to observe the placebo responders. During the next 8 weeks, 18 of the men, selected at random, received testosterone undecanoate (TU) (80 mg at 8 a.m. and 40 mg at 8 p.m.) while the remaining men continued to receive placebo. This phase of the study was double-blind. Then all men received placebo on a single-blind basis for 2 weeks to observe "withdrawal" effects, followed by an 8-week observation period without any medication. The 16 patients studied in Munich were seen again at regular intervals for 1 year.
Effects of TU on Impotent Males
473
Throughout the study a rating scale similar to the Clinical Global Impressions Scale (National Institute of Mental Health, 1976) was used to measure therapeutic effects. The scale was administered every other week. A therapeutic effect was considered to have occurred when the man reported a clearly increased capability to have a penile erection, resulting in more satisfactory sexual intercourse. A score of 1-3 in the rating score corresponded to a therapeutic effect (Benkert, 1977). A detailed sexual history was obtained from each man prior to the study, and self-rating scales for depression (Befindlichkeits-Skale, "B-S") and for somatic disturbances (Beschwerdeliste, "B-L") were filled out weekly by each man during the study (yon Zerssen and Koeller, 1976a, b). The men studied in Munich were given psychological tests (d2 test) (Brickenkamp, 1975), the figure symbol test, and the mosaic test of HAWIE (Wechsler, 1964) before and after the treatment period. They were also rated for anxiety using the Hamiltonanxiety-rating scale (HAMA) (Hamilton, 1959). Blood samples for determination of total testosterone (T), free T fraction, 5c~-dihydrotestosterone (DHT), sex hormone binding globulin (SHBG), estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin (PRL) and for laboratory tests were drawn in the morning between 8 and 9.30 a.m. before the first placbeo period and after the 10th week of study. Another blood sample was taken after the 12th week for determination of T and routine laboratory tests. Blood samples for the LHRH test were taken at - 5 , 10, 25, and 45 min before or after a rapid intravenous injection of 100 bLg LHRH. The concentration of LH, FSH, and PRL in the plasma was measured by radioimmunoassay using double antibody techniques (Joel et al., 1974). LER 907 served as the standard reference preparation for LH and FSH while PRL was measured with a V-L-S kit No. 1. Steroid measurements were performed with specific radioimmunoassays (Friedrich et al., 1974).. SHBG was determined according to a modification of the method of Mickelson and Petra (1974), and the free T fraction was determined according to the method of Tremblay and Dube (1974). Statistical analysis was done using Student's t test for dependent and independent samples. Standard deviations are given.
RESULTS
Effect of TU on Sexual Impotency
Twenty-nine of the men completed the study: 13 in the TU group and 16 in the placebo group. Four men left the study because of somatic diseases or social factors independent of the medication. Side effects (vegetative complaints) in two men in the placebo group and in one man in the TU group caused
474
9
Benkert, Witt, Adam, and Leitz
_~ T U ( n : 1 3 ) * ....... *
PL(n--161
.®'"
,II
8
.
........
7 6 5 4 3
/ ,/
2 1
2
LpL I
4
6
Tu/P L
8
10
12 W
I[_p L-I
Fig. 1. Effect of TU and placebo (PL) on impotence in 29 men. The therapeutic effects shown refer to the preceding 2 weeks (w) of treatment. The ordinate represents the number of patients who reported an improvement in potency.
them to leave the study, although no pathological values were found in these men on routine laboratory tests carried out after the 10th and 12th weeks of the study. Five of the 29 men who completed the study showed a therapeutic effect after the first 2 weeks of placebo treatment (Fig. 1); four of these men were randomly assigned to further placebo treatment while the remaining man was assigned to treatment with TU. During the next 8 weeks an additional four men in the placebo group as well as four men in the TU group showed a therapeutic effect. During the 2 following weeks of placebo treatment, one more man in the placebo group and three men from the TU group showed a therapeutic effect. Thus a therapeutic effect occurred in 17 of the 29 men (58.6%) during the 12 weeks of medication (Fig. 1). Twelve of the men studied in Munich showed a therapeutic effect after 12 weeks of treatment; six of them were in the placebo group and six were in the TU group. Eleven of these men were seen at regular intervals in a 1-year follow-up study. Three (one from the TU group and two from the placebo group) reported that the therapeutic effect had stopped by 2 months after
Effects of TU on Impotent Males
475
treatment; four (three men given TU and one man given placebo) reported that the therapeutic effect lasted from 4 to 5 months after treatment; two (one man given TU and one given placebo) said that the effect lasted 9-10 months; while two given only placebo reported that the therapeutic effect had lasted throughout the year. Effect of TU on the Hypothalamic-Pituitary-Gonadal A x i s Administration of TU for 8 weeks decreased the concentration of T in plasma significantly (Table I, 10th week, p < 0.05). The plasma T level was normal again 2 weeks after cessation o f TU treatment (12th week). The control T levels in the two groups did not differ significantly. Administration of TU failed to affect the levels of DHT and E 2 significantly. The free T fraction and the SHBG were measured in five men given TU and eight men given placebo. Administration of TU for 8 weeks decreased SHBG levels significantly (p < 0.01) and tended to increase the free T fraction. SHBG levels tended to increase and free T fraction tended to decrease 2 weeks after cessation of TU treatment, but neither of these changes was statistically significant. No significant differences were observed between the effect of TU and placebo on baseline levels of LH, FSH and PRL or on the LHRH-induced LH/ FSH response (Fig. 2). No correlations were found between the therapeutic effect of treatment and the basal hormonal data.
Effect of TU on Depression Scores and Performance Tests Depression scores were in the normal range in all the men, except three (one in the TU group and two in the placebo group) who showed elevated scores ( > 30). No significant differences occurred between depression scores in
Table I. Total Plasma Testosterone Level Before (Control) and After 8 Weeks of TU or Placebo (PL) Treatment (10th Week) as Well as After 2 Final Weeks of PL Medication in AU Patients (12th Week) Testosterone (ng/100 ml) TU PL
Control
10th week
12th week
n
579 +- 186 a 495 -+204
435 -+209 a 481 -+ 122
506 -+298 477 -+ 128
13 16
ap < 0.05.
476
Benkert, Witt, Adam, and Leitz &--&after
TU/
•,---.,before
PL
i~
400-
300-
v ,.r. ,-I
/
200-
///
//t//
j/ ~
100.
/J
JJ
j/
~
0. 0
25 PL-
45
rain
0
25
GROUP (n:14)
TU-GROUP(n
45
rain :13)
800 -
700 -
x Aafter TU/PL = - - - e be[o re /i
600,
A
oi
500-
400-
300"
200 -
b"
100 -
O.
2=5 PL
GROUP
(n:14)
4=5 rain
r 0 TU-GROUP
1"---===-'~ 25 45 mln (n :13)
Fig. 2. LHRH-induced LH (top)/FSH (bottom) response 25 and 45 min after an i.v. injection of 100 /~g LHRH given immediately after a blood sample was drawn at t = o min. The response was measured in the placebo (PL) and TU groups before and after TU or placebo medication.
Effects of TU on Impotent Males
477
men given TU and placebo. The somatic score, which provides a measure of complaints of somatic symptoms, fell significantly during treatment in both groups (from 22.5 -+ 16.4 to 14.5 -+ 13.7 in the TU group and from 19.4 -+ 12.1 to 12.5 + 14.2 in the placebo group) with no significant differences between groups. The additional tests administered to men in Munich showed psychic and somatic anxiety scores to decrease similarly and all three performance test scores to improve similarly during treatment in TU and placebo groups. Thus 8 weeks of TU treatment failed to have any specific effects on the rating scale and performance test scores.
DISCUSSION TU was chosen for use because it is an orally effective T preparation. T is ineffective when given orally because after absorption it is transported via the portal vein and rapidly inactivated by the liver. In contrast, TU is orally active because it is partly absorbed via the lymphatic system, thus by passing the liver. After absorption, TU is hydrolized in the periphery to T (Coert et al., 1975; Horst et al., 1976). Previous studies have found good therapeutic effects of TU at daily doses between 40 and 240 mg as an androgen substitute in sexually impotent, hypogonadal men (Hirschla~user et al., 1975; Franchi et al., 1978). The main finding of the present study is that administration of TU at a dose of 120 mg per day for 8 weeks to sexually impotent men without androgen deficiency failed to have a better therapeutic effect than placebo. More than half of the men reported a marked improvement of their sexual potency during the 12-week study, regardless of whether they received TU or placebo. TU treatment also failed to differ from placebo in effects on hypothalamic-pituitarygonadal functions and psychological tests in the patients. These findings suggest that TU offers no advantages over placebo in the treatment of sexual impotence of men without androgen deficiency. An unexpected finding was a fall, rather than a rise, in the total T level in the patients after 8 weeks of treatment with TU. This situation contrasts to the rise in T levels seen in hypogonadal men as well as in healthy young men given TU on a short-term or long-term basis (Hirschh/iuser et al., 1975; Horst et al., 1976; Nieschlag et aL, 1975, 1977; Franchimont et al., 1978; Franchi et al., 1978; Mies and Kicovic, 1977). While the present data are insufficient to provide an explanation for the fall in total T levels, one may speculate that administration of TU to sexually impotent men without androgen deficiency caused either the endogeneous production of T to decrease or the metabolic clearance of T to rise. Evidence against a fall in the production of T during TU treatment comes from the failure of the treatment to suppress LH in the patients. On the other hand, evidence for a change in clearance of T during TU treatment comes from the fact that the SHBG level fell and the free T fraction rose. A fall in SHBG is a
478
Benkert, Witt, Adam, and Leitz
normal effect of androgen administration (Anderson, t974) and leads to a rise in the free T fraction. Free T may be readily metabohzed so that the metabolic clearance rate of T may be increased and the total T level may fall. Further endocrinological studies are needed, however, to clarify the effects of longterm pharmacotherapy with androgens in sexually impotent patients without androgen deficiency.
REFERENCES Anderson, D. C. (1974). Sex-hormone-binding globulin. Clin. EndocrinoL 3: 69-95. Benkert, O. (1977). Sexuelle Impotenz: Neuroendokrinologische und pharmakothera. peutische Untersuchungen, Springer, Heidelberg. Benkert, O. (1979). Pharmacotherapy of sexual impotence in the male.Mod. ProbL Pharrn. 15 (in press). Benkert, O., Jordan, R., Dahlen, H. G., Schneider, H. P. G., and Gammel, G. (1975). Sexual impotence: A double-blind study of LHRH nasal spray versus placebo. Neuropsychobiology 1: 203-210. Brickenkamp, R. (1975). Test d2: Aufmerksamkeits-Belastungstest, Verlag f~ir Psychologie, G6ttingen. Coert, A., Geelen, J., de Visser, J., and van der Vies, J. (1975). The pharmacology and metabolism of testosterone undecanoate (TU), a new orally active androgen. Acta Endoerinol. 79: 789-800. Franchi, F., Luisi, M., and Kicovic, P. M. (1978). Long-term study of oral testosterone undecanoate in hypogonadal males. Int. J. Androl. 1: 270-278. Franchimont, P., Kicovic, P. M., Mattei, A., and Roulier, R. (1978). Effect of oral testosterone undecanoate in hypogonadal male patients, Clin. Endocrinol. 9: 313-320. Friedrich, E., Jaeger-Whitegiver, E. R., Bieder, M., Halverscheidt, H., Penki, B., Pallat, P., KeUer, E., and Schindler, A. E. (i974). Standardization of specific radioimmunassays for plasma estrone, estradiol, progesterone and androstenedione. J. Steroid Biochem. 5: 305. Hamilton, M. (1959). The assessment of anxiety states by rating. Br. J. Med. Psychol. 32: 50-52. Hirschh~user, C., Hopkinson, C. R. N., Sturm, G., and Coert, A. (1975). Testosterone undecanoate: A new orally active androgen. Acta EndocrinoL 80: 179-187. Horst, H.-J., H61tje, W. J., Dennis, M., Coert, A., Geelen, J., and Voigt, K. D. (1976) Lymphatic absorption and metabolism of orally administered testosterone undecanoate in man. Klin. Wochenschr. 54: 875-879. Joel, F. W., Schoenberg, C. K., Ilg, W., and Keller, E. (1974). Problems of optimization of double antibody radioimmunoassay of HLH, HFN and HGH. In Radioimmunassay and Related Procedures in Medicine, Vol. I, International Atomic Energy Agency, Vienna. Mickel~on, K. E., and Petra, P. H. (1974). A filter assay for the sex steroid binding protein (SBP) of human serum. FEBS Lett. 44:34-38. Mies, R., and Kicovic, P. M. (1977). Effects of TU administration on LH and FSH response during the standard LHRH test in healthy male volunteers. Andrologia 9(3): 233-236. National Institute of Mental Health (1976). 028 CGI: Clinical global impressions. In Guy, W. (ed.), ECDEU Assessment Manual for Psychopharmacology, rev. ed., Rockvflle, Md., pp. 217-222. Neumann, F., and Steinbeck, H. (1971). Antiandrogene: Tierexperimentelle Grundlagen und klinische Anwendungsm6glichkeiten. Internist 12: 198-205. Nieschlag, E., Marts, J., and Kicovic, P. (1975). Plasma androgen levels in man after oral administration of testosterone or testosterone undecanoate. Acta Endocrinol. 79: 366-374.
Effects of TU on Impotent Males
479
Nieschlag, E., C/ippers, H. J., and Wickings, E. J. (1977). Influence of sex, testicular development and liver function on the bioavailability of oral testosterone. Eur. J. CIin. Invest. 7: 145. Tremblay, R. R., and Dube, J. Y. (1974). Plasma concentration of free and non-TeBG bound testosterone in women on oral contaceptives. Contraception 10: 599-605. Vermeulen, A., Verdonck, L., and yon der Straeten, M. (1969). Capacity of the testosteronebinding globulin in human plasma and influence of specific binding of testosterone on its metabolic clearance rate. J. Clin. Endocrinol. 29: 1470-1480. yon Zerssen, D., and Koeller, D. M. (1976a). Die Beschwerden-Liste, Beltz, Weinheim. yon Zerssen, D., and Koeller, D. M. (1976b). Die Befindlichkeits-Skala, Beltz, Weinheim. Wechsler, D. (1964). Die Messung der Intelligenz Erwachsener, Huber, Bern-Stuttgart.
Effects of Testosterone Undecanoate on Sexual Potency and the Hypothalamic-Pituitary-Gonadal Axis of Impotent Males O. Benkert, 1 W. Witt, x W. Adam, 2 and A. Leitz 2
A double-blind comparison was made of the effects of testosterone undecanoate (TU) and placebo on sexual potency of 29 impotent men ages 45-75. The main criteria for inclusion in the study were a reduced or nonexistent capacity to have an erection during intercourse and no clinical signs of endocrinological pathology. All patients received placebo for 2 weeks. Then TU was given at a daily dose of 120 mg to 13 patients selected at random while the other patients continued to receive placebo. After 8 weeks all patients received placebo again for 2 weeks. An improvement in sexual potency was reported by five patients given TU and eight patients given placebo, with no significant differences between the groups. Treatment with TU influenced neither the hypothalamic-pituitary-gonadal axis, as judged by levels of prolactin, LH, FSH, and the LHRH-induced LH/FSH response, nor depression, anxiety, and somatic scores or performance tests. The only specific effect of TU treatment was to decrease the total plasma testosterone level. The present findings show pharmacotherapy with androgens to be no more effective than placebo in restoring sexual potency to sexually impotent men without androgen deficiency. Further studies may be needed to elucidate fully the effects of androgen administration on psychological and endocrinological variables in such patients. KEY WORDS: impotence; hypothalamic-pituitary-gonadal axis; testosterone undecanoate; androgen substitu~tion; sexual dysfunction; p sychoneuroendocrinology.
1 Psychiatric Clinic of the University of Munich, Nussbaumstrasse, 7, D-8000 M~nchen 2,
West Germany. 2 Andrologic Clinic of the University of Tiibingen, Tfibingen, West Germany. 471 0004-0002/79/1100-0471 $3.00/0 © 1979 Plenum Publishing Corporation
472
Benkert, Witt, Adam, and Leitz INTRODUCTION
Sexual impotence of some males is due to a deficiency of androgens, and administration of androgens to these men usually restores their potency (Neumann and Steinbeck, 1971). Sexual impotence can also occur in males without a demonstrable lack of androgens, and no pharmacotherapy has been shown to reliably restore their sexual potency (Benkert, 1979). Nevertheless, androgens are often prescribed to treat sexual impotence of males without signs of androgen deficiency. Since only a few pilot studies have been carried out to investigate effects of androgen therapy on non-androgen-dependent sexual impotence, the value of this treatment is uncertain. The present investigation was to determine on a large-scale, blind basis whether androgen treatment influences sexual impotenc e in males without clinical signs of androgen deficiency. Studies on the effects of androgen treatment on the hypothalamic,pituitary-gonadal axis and psychological functions of the men were performed as well.
PATIENTS AND METHODS The study was carried out on 36 males between ages 45 and 75 years old (mean age 56.5 years) who had sought treatment for sexual impotence, either at the Psychiatric Clinic of the University of Munich or at the Andrologic Clinic of the University of Tubingen. The main criteria for inclusion were a diagnosis of sexual impotence with reduced or nonexistent ability to have an erection during intercourse, a dysfunction persistent for at least 1 year, due to unknown etiology, and a prior history of normal penile erection (Benkert et al., 1975). Additional criteria for inclusion of men under 60 years old (17 in all) were (1) a regular female sexual partner, (2) at least one attempt at coitus per week, and (3) normal findings in an andrological examination including spermiogram of samples obtained by masturbation. All the men showed normal values in a neurological examination including EEG and X-ray of the skull and a clinical endocrinological examination (i.e., somatic examination and anamnesis), and none had psychosis or acute conflict with their sex partner at the time of the study. Each man gave his informed consent to participate in the study. The study lasted 20 weeks. During the first 2 weeks, all men received placebo (two capsules in the morning and one capsule in the evening) in a single-blind fashion to observe the placebo responders. During the next 8 weeks, 18 of the men, selected at random, received testosterone undecanoate (TU) (80 mg at 8 a.m. and 40 mg at 8 p.m.) while the remaining men continued to receive placebo. This phase of the study was double-blind. Then all men received placebo on a single-blind basis for 2 weeks to observe "withdrawal" effects, followed by an 8-week observation period without any medication. The 16 patients studied in Munich were seen again at regular intervals for 1 year.
Effects of TU on Impotent Males
473
Throughout the study a rating scale similar to the Clinical Global Impressions Scale (National Institute of Mental Health, 1976) was used to measure therapeutic effects. The scale was administered every other week. A therapeutic effect was considered to have occurred when the man reported a clearly increased capability to have a penile erection, resulting in more satisfactory sexual intercourse. A score of 1-3 in the rating score corresponded to a therapeutic effect (Benkert, 1977). A detailed sexual history was obtained from each man prior to the study, and self-rating scales for depression (Befindlichkeits-Skale, "B-S") and for somatic disturbances (Beschwerdeliste, "B-L") were filled out weekly by each man during the study (yon Zerssen and Koeller, 1976a, b). The men studied in Munich were given psychological tests (d2 test) (Brickenkamp, 1975), the figure symbol test, and the mosaic test of HAWIE (Wechsler, 1964) before and after the treatment period. They were also rated for anxiety using the Hamiltonanxiety-rating scale (HAMA) (Hamilton, 1959). Blood samples for determination of total testosterone (T), free T fraction, 5c~-dihydrotestosterone (DHT), sex hormone binding globulin (SHBG), estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin (PRL) and for laboratory tests were drawn in the morning between 8 and 9.30 a.m. before the first placbeo period and after the 10th week of study. Another blood sample was taken after the 12th week for determination of T and routine laboratory tests. Blood samples for the LHRH test were taken at - 5 , 10, 25, and 45 min before or after a rapid intravenous injection of 100 bLg LHRH. The concentration of LH, FSH, and PRL in the plasma was measured by radioimmunoassay using double antibody techniques (Joel et al., 1974). LER 907 served as the standard reference preparation for LH and FSH while PRL was measured with a V-L-S kit No. 1. Steroid measurements were performed with specific radioimmunoassays (Friedrich et al., 1974).. SHBG was determined according to a modification of the method of Mickelson and Petra (1974), and the free T fraction was determined according to the method of Tremblay and Dube (1974). Statistical analysis was done using Student's t test for dependent and independent samples. Standard deviations are given.
RESULTS
Effect of TU on Sexual Impotency
Twenty-nine of the men completed the study: 13 in the TU group and 16 in the placebo group. Four men left the study because of somatic diseases or social factors independent of the medication. Side effects (vegetative complaints) in two men in the placebo group and in one man in the TU group caused
474
9
Benkert, Witt, Adam, and Leitz
_~ T U ( n : 1 3 ) * ....... *
PL(n--161
.®'"
,II
8
.
........
7 6 5 4 3
/ ,/
2 1
2
LpL I
4
6
Tu/P L
8
10
12 W
I[_p L-I
Fig. 1. Effect of TU and placebo (PL) on impotence in 29 men. The therapeutic effects shown refer to the preceding 2 weeks (w) of treatment. The ordinate represents the number of patients who reported an improvement in potency.
them to leave the study, although no pathological values were found in these men on routine laboratory tests carried out after the 10th and 12th weeks of the study. Five of the 29 men who completed the study showed a therapeutic effect after the first 2 weeks of placebo treatment (Fig. 1); four of these men were randomly assigned to further placebo treatment while the remaining man was assigned to treatment with TU. During the next 8 weeks an additional four men in the placebo group as well as four men in the TU group showed a therapeutic effect. During the 2 following weeks of placebo treatment, one more man in the placebo group and three men from the TU group showed a therapeutic effect. Thus a therapeutic effect occurred in 17 of the 29 men (58.6%) during the 12 weeks of medication (Fig. 1). Twelve of the men studied in Munich showed a therapeutic effect after 12 weeks of treatment; six of them were in the placebo group and six were in the TU group. Eleven of these men were seen at regular intervals in a 1-year follow-up study. Three (one from the TU group and two from the placebo group) reported that the therapeutic effect had stopped by 2 months after
Effects of TU on Impotent Males
475
treatment; four (three men given TU and one man given placebo) reported that the therapeutic effect lasted from 4 to 5 months after treatment; two (one man given TU and one given placebo) said that the effect lasted 9-10 months; while two given only placebo reported that the therapeutic effect had lasted throughout the year. Effect of TU on the Hypothalamic-Pituitary-Gonadal A x i s Administration of TU for 8 weeks decreased the concentration of T in plasma significantly (Table I, 10th week, p < 0.05). The plasma T level was normal again 2 weeks after cessation o f TU treatment (12th week). The control T levels in the two groups did not differ significantly. Administration of TU failed to affect the levels of DHT and E 2 significantly. The free T fraction and the SHBG were measured in five men given TU and eight men given placebo. Administration of TU for 8 weeks decreased SHBG levels significantly (p < 0.01) and tended to increase the free T fraction. SHBG levels tended to increase and free T fraction tended to decrease 2 weeks after cessation of TU treatment, but neither of these changes was statistically significant. No significant differences were observed between the effect of TU and placebo on baseline levels of LH, FSH and PRL or on the LHRH-induced LH/ FSH response (Fig. 2). No correlations were found between the therapeutic effect of treatment and the basal hormonal data.
Effect of TU on Depression Scores and Performance Tests Depression scores were in the normal range in all the men, except three (one in the TU group and two in the placebo group) who showed elevated scores ( > 30). No significant differences occurred between depression scores in
Table I. Total Plasma Testosterone Level Before (Control) and After 8 Weeks of TU or Placebo (PL) Treatment (10th Week) as Well as After 2 Final Weeks of PL Medication in AU Patients (12th Week) Testosterone (ng/100 ml) TU PL
Control
10th week
12th week
n
579 +- 186 a 495 -+204
435 -+209 a 481 -+ 122
506 -+298 477 -+ 128
13 16
ap < 0.05.
476
Benkert, Witt, Adam, and Leitz &--&after
TU/
•,---.,before
PL
i~
400-
300-
v ,.r. ,-I
/
200-
///
//t//
j/ ~
100.
/J
JJ
j/
~
0. 0
25 PL-
45
rain
0
25
GROUP (n:14)
TU-GROUP(n
45
rain :13)
800 -
700 -
x Aafter TU/PL = - - - e be[o re /i
600,
A
oi
500-
400-
300"
200 -
b"
100 -
O.
2=5 PL
GROUP
(n:14)
4=5 rain
r 0 TU-GROUP
1"---===-'~ 25 45 mln (n :13)
Fig. 2. LHRH-induced LH (top)/FSH (bottom) response 25 and 45 min after an i.v. injection of 100 /~g LHRH given immediately after a blood sample was drawn at t = o min. The response was measured in the placebo (PL) and TU groups before and after TU or placebo medication.
Effects of TU on Impotent Males
477
men given TU and placebo. The somatic score, which provides a measure of complaints of somatic symptoms, fell significantly during treatment in both groups (from 22.5 -+ 16.4 to 14.5 -+ 13.7 in the TU group and from 19.4 -+ 12.1 to 12.5 + 14.2 in the placebo group) with no significant differences between groups. The additional tests administered to men in Munich showed psychic and somatic anxiety scores to decrease similarly and all three performance test scores to improve similarly during treatment in TU and placebo groups. Thus 8 weeks of TU treatment failed to have any specific effects on the rating scale and performance test scores.
DISCUSSION TU was chosen for use because it is an orally effective T preparation. T is ineffective when given orally because after absorption it is transported via the portal vein and rapidly inactivated by the liver. In contrast, TU is orally active because it is partly absorbed via the lymphatic system, thus by passing the liver. After absorption, TU is hydrolized in the periphery to T (Coert et al., 1975; Horst et al., 1976). Previous studies have found good therapeutic effects of TU at daily doses between 40 and 240 mg as an androgen substitute in sexually impotent, hypogonadal men (Hirschla~user et al., 1975; Franchi et al., 1978). The main finding of the present study is that administration of TU at a dose of 120 mg per day for 8 weeks to sexually impotent men without androgen deficiency failed to have a better therapeutic effect than placebo. More than half of the men reported a marked improvement of their sexual potency during the 12-week study, regardless of whether they received TU or placebo. TU treatment also failed to differ from placebo in effects on hypothalamic-pituitarygonadal functions and psychological tests in the patients. These findings suggest that TU offers no advantages over placebo in the treatment of sexual impotence of men without androgen deficiency. An unexpected finding was a fall, rather than a rise, in the total T level in the patients after 8 weeks of treatment with TU. This situation contrasts to the rise in T levels seen in hypogonadal men as well as in healthy young men given TU on a short-term or long-term basis (Hirschh/iuser et al., 1975; Horst et al., 1976; Nieschlag et aL, 1975, 1977; Franchimont et al., 1978; Franchi et al., 1978; Mies and Kicovic, 1977). While the present data are insufficient to provide an explanation for the fall in total T levels, one may speculate that administration of TU to sexually impotent men without androgen deficiency caused either the endogeneous production of T to decrease or the metabolic clearance of T to rise. Evidence against a fall in the production of T during TU treatment comes from the failure of the treatment to suppress LH in the patients. On the other hand, evidence for a change in clearance of T during TU treatment comes from the fact that the SHBG level fell and the free T fraction rose. A fall in SHBG is a
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normal effect of androgen administration (Anderson, t974) and leads to a rise in the free T fraction. Free T may be readily metabohzed so that the metabolic clearance rate of T may be increased and the total T level may fall. Further endocrinological studies are needed, however, to clarify the effects of longterm pharmacotherapy with androgens in sexually impotent patients without androgen deficiency.
REFERENCES Anderson, D. C. (1974). Sex-hormone-binding globulin. Clin. EndocrinoL 3: 69-95. Benkert, O. (1977). Sexuelle Impotenz: Neuroendokrinologische und pharmakothera. peutische Untersuchungen, Springer, Heidelberg. Benkert, O. (1979). Pharmacotherapy of sexual impotence in the male.Mod. ProbL Pharrn. 15 (in press). Benkert, O., Jordan, R., Dahlen, H. G., Schneider, H. P. G., and Gammel, G. (1975). Sexual impotence: A double-blind study of LHRH nasal spray versus placebo. Neuropsychobiology 1: 203-210. Brickenkamp, R. (1975). Test d2: Aufmerksamkeits-Belastungstest, Verlag f~ir Psychologie, G6ttingen. Coert, A., Geelen, J., de Visser, J., and van der Vies, J. (1975). The pharmacology and metabolism of testosterone undecanoate (TU), a new orally active androgen. Acta Endoerinol. 79: 789-800. Franchi, F., Luisi, M., and Kicovic, P. M. (1978). Long-term study of oral testosterone undecanoate in hypogonadal males. Int. J. Androl. 1: 270-278. Franchimont, P., Kicovic, P. M., Mattei, A., and Roulier, R. (1978). Effect of oral testosterone undecanoate in hypogonadal male patients, Clin. Endocrinol. 9: 313-320. Friedrich, E., Jaeger-Whitegiver, E. R., Bieder, M., Halverscheidt, H., Penki, B., Pallat, P., KeUer, E., and Schindler, A. E. (i974). Standardization of specific radioimmunassays for plasma estrone, estradiol, progesterone and androstenedione. J. Steroid Biochem. 5: 305. Hamilton, M. (1959). The assessment of anxiety states by rating. Br. J. Med. Psychol. 32: 50-52. Hirschh~user, C., Hopkinson, C. R. N., Sturm, G., and Coert, A. (1975). Testosterone undecanoate: A new orally active androgen. Acta EndocrinoL 80: 179-187. Horst, H.-J., H61tje, W. J., Dennis, M., Coert, A., Geelen, J., and Voigt, K. D. (1976) Lymphatic absorption and metabolism of orally administered testosterone undecanoate in man. Klin. Wochenschr. 54: 875-879. Joel, F. W., Schoenberg, C. K., Ilg, W., and Keller, E. (1974). Problems of optimization of double antibody radioimmunoassay of HLH, HFN and HGH. In Radioimmunassay and Related Procedures in Medicine, Vol. I, International Atomic Energy Agency, Vienna. Mickel~on, K. E., and Petra, P. H. (1974). A filter assay for the sex steroid binding protein (SBP) of human serum. FEBS Lett. 44:34-38. Mies, R., and Kicovic, P. M. (1977). Effects of TU administration on LH and FSH response during the standard LHRH test in healthy male volunteers. Andrologia 9(3): 233-236. National Institute of Mental Health (1976). 028 CGI: Clinical global impressions. In Guy, W. (ed.), ECDEU Assessment Manual for Psychopharmacology, rev. ed., Rockvflle, Md., pp. 217-222. Neumann, F., and Steinbeck, H. (1971). Antiandrogene: Tierexperimentelle Grundlagen und klinische Anwendungsm6glichkeiten. Internist 12: 198-205. Nieschlag, E., Marts, J., and Kicovic, P. (1975). Plasma androgen levels in man after oral administration of testosterone or testosterone undecanoate. Acta Endocrinol. 79: 366-374.
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Nieschlag, E., C/ippers, H. J., and Wickings, E. J. (1977). Influence of sex, testicular development and liver function on the bioavailability of oral testosterone. Eur. J. CIin. Invest. 7: 145. Tremblay, R. R., and Dube, J. Y. (1974). Plasma concentration of free and non-TeBG bound testosterone in women on oral contaceptives. Contraception 10: 599-605. Vermeulen, A., Verdonck, L., and yon der Straeten, M. (1969). Capacity of the testosteronebinding globulin in human plasma and influence of specific binding of testosterone on its metabolic clearance rate. J. Clin. Endocrinol. 29: 1470-1480. yon Zerssen, D., and Koeller, D. M. (1976a). Die Beschwerden-Liste, Beltz, Weinheim. yon Zerssen, D., and Koeller, D. M. (1976b). Die Befindlichkeits-Skala, Beltz, Weinheim. Wechsler, D. (1964). Die Messung der Intelligenz Erwachsener, Huber, Bern-Stuttgart.
