0021 -972X/90/7003-0792$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1990 by The Endocrine Society
Vol. 70, No. 3 Printed in U.S.A.
Testosterone Replacement Therapy and Sleep-Related Erections in Hypogonadal Men GLENN R. CUNNINGHAM, MAX HIRSHKOWITZ, STANLEY G. KORENMAN, AND ISMET KARACAN Medical (G.R.C.), Research (G.R.C., MM.), and Psychiatry (I.K.) Services, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas 77030; the Medical Service, Veterans Affairs Medical Center (S.G.K.), Sepulvada, California 91343; and University of California (S.G.K.), Los Angeles, California 90024
ABSTRACT. Hypogonadal men usually have diminished libido and erectile dysfunction, and testosterone replacement therapy in these men increases sexual activity, erotic thoughts, and self-reported nocturnal erections. The polygraphlc assessment of nocturnal penile tumescence (NPT) provides an objective index of erectile capability and is useful for differentiating psychogenic from organic erectile dysfunction. In this study we evaluated NPT in six hypogonadal adult men during and after termination of androgen therapy. Multinight sleep studies were conducted within 1 week and 7-8 weeks after each man received 200 mg testosterone cypionate, im. The mean serum testosterone level 4-7 days after testosterone injection was 35.9 ± 3.4 (±SE) nmol/L, and it fell to 2.3 ± 0.9 nmol/L after 7-8 weeks. Signif-
icant declines (P < 0.05) in the number of NPT episodes (3.7 to 2.0), maximum penile circumference increase (24 to 13 mm), and total tumescence time (107 to 55 min) accompanied the fall in the serum testosterone level. No androgen-related changes in the amount or integrity of rapid eye movement sleep were found. Finally, the mean penile rigidity (buckling pressure) decreased from 770 ± 98 to 590 ± 81 g (P < 0.05). Comparison of these results to those in normal men revealed that none of these men met all diagnostic criteria for organic impotence, even 7-8 weeks after discontinuation of testosterone administration. While men with androgen deficiency may have normal NPT, sleep-related erections increase in response to testosterone administration. (J Clin Endocrinol Metab 70: 792, 1990)
H
and free testosterone levels, but no relationship between NPT and serum FSH, LH, sex-hormone binding globulin, or PRL concentrations. Few studies have evaluated changes in sleep-related erections during testosterone therapy in hypogonadal men. In a study of six hypogonadal men, using portable home NPT monitors, administration of 200 mg testosterone enanthate, im, prolonged the time that the increase in penile circumference exceeded 15 mm (10). In another report, four hypogonadal men were studied before and during daily treatment with up to 160 mg testosterone undecanoate, orally, (11). Treatment increased penile circumference and total tumescence time and reduced the latency period before the first erection. The number of NPT episodes, however, did not change. Since measurement of NPT in hypogonadal men has been limited, we undertook this study to determine the relationship between androgen replacement therapy and changes in sleep-related erections. Laboratory polysomnography was used to avoid problems associated with home monitoring devices (12,13), and multinight recordings with erectile measures derived from both the penile base and tip (at the coronal sulcus) were made. Since penile rigidity is a critical measure of erectile activity (14-16), it also was assessed.
YPOGONADISM in men usually results in loss of both libido and potency (1), which can be restored by adequate testosterone replacement therapy. Specifically, self-reported measures of libido, nocturnal erections, and potency increase when hypogonadal men are treated with testosterone enanthate (2, 3) and testosterone undecanoate (4). However, objective documentation of such improvement is limited. Measurements of nocturnal penile tumescence (NPT) provide an objective and quantitative method for evaluating changes in erectile pattern. Furthermore, assessment of NPT is useful for the differentiation of organic from psychogenic erectile dysfunction (5-7). In a study of 172 men with complaints of erectile dysfunction and no history of testicular disease, 6 were identified as androgen deficient; all 6 had diminished NPT (8). Fenwick and co-workers (9) evaluated NPT and serum testosterone levels in 10 men with chronic epilepsy, 5 of whom had low-normal serum testosterone levels. They found positive correlations between NPT and serum total Received November 7, 1989. Address all correspondence and requests for reprints to: Glenn R. Cunningham, M.D., Veterans Administration Medical Center-lllE, 2002 Holcombe Boulevard, Houston, Texas 77030.
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TESTOSTERONE AND SLEEP-RELATED ERECTIONS
Materials and Methods Patients Six hypogonadal men, aged 33-56 yr, were studied at the Baylor Sleep Disorders and Research Center (see Table 1). These men had received 200 mg testosterone cypionate, im, every 2-4 weeks for 3-18 yr before the study. All men reported normal and satisfactory sexual activity while receiving androgen replacement. The protocol was approved by the institutional review board, and each man gave written and oral informed consent. Procedures The first study period began 1-4 days after a man received 200 mg testosterone cypionate, im. The second study period was conducted 7-8 weeks later, with there having been no interim androgen replacement. By this time all men had been androgen deficient for at least 1 month. During the week before the second study period, the men wore a scrotal patch which contained no medication but was of the same design as those patches that do contain testosterone. The men were told that some patches would not contain testosterone and others would contain varied amounts of testosterone. During each study period the men were evaluated in the sleep laboratory for 3 consecutive nights. The first night of each session was used to acclimate (or reacclimate) the men to the laboratory. Sleep stages were scored from electroencephalographic, electrooculographic, and submental electromyographic tracings according to standard techniques (17) in which each minute of the record was classified as awake (stage 0), sleep stage 1,2,3, 4, or rapid eye movement (REM). Respiratory pattern was recorded with an abdominal strain gauge to measure diaphragmatic movement and a nasal-nasal/oral temperature sensor to measure air flow. Heart rate was recorded using precordial electrodes. NPT was assessed concurrently by measuring changes in penile circumference with strain gauges (mercury-filled rubber tubing) placed around the base and at the
793
coronal sulcus (tip) of the penis. A NPT episode was defined as a period during which the circumference at the base or tip increased by 2 mm or greater for 20 or more s [see Karacan (14) for details on standardized NPT scoring]. This scoring system avoids errors of omission when incomplete or partial tumescence episodes occur. Total tumescence time is the total time with tumescence for the night. All recordings were made using Grass model 78 polygraphs (Grass Instrument Co., Quincey, Houston, TX). NPT was recorded using AMS (American Medical Systems, Houston, TX) and TME (Texas Medical Electronics, Houston, TX)) NPT monitors interfaced to the polygraph. On one or more of the sleep-recording nights, the men were awakened during an episode of tumescence for measurement of penile rigidity (buckling force). In this procedure, force is applied to the tip of the penis and the pressure (measured in grams) required to bend the penile shaft 30° is determined. A penile rigidity of 500 g or greater has been empirically estimated as the minimum rigidity needed for vaginal intercourse (18). During the third night blood samples were obtained throughout the night by a constant withdrawal of blood from a forearm iv catheter. The samples were collected for 20-min intervals. Serum total and bloavailable testosterone, dihydrotestosterone, and estradiol concentrations were measured by RIA in the three samples collected 1, 3, and 5 h after bedtime (19-21). The bioavailable hormone concentration was measured by addition of [3H]testosterone, [3H]dihydrotestosterone, or [3H]estradiol and precipitation of the hormone-sex hormone-binding globulin complex with ammonium sulfate. The total hormone concentration was multiplied by the fraction of labeled hormone not precipitated to give the bioavailable concentration. Hormonal measurements were performed in the laboratory of Dr. S. G. Korenman. All samples from an individual man were analyzed in duplicate in the same assay. The intraassay variability for each of these assays was less than 6%, and the interassay variability was less than 8%. Sleep parameters and data analysis The sleep efficiency index (SEI) was calculated for each man for each night. It is the ratio of total sleep time to time in bed,
TABLE 1. Clinical characteristics of the six hypogonadal men Patient no.
Age (yrs)
1 2
33 36
3
37
4
34
5 6
56 53
Diagnosis Klinefelter's syndrome Pituitary tumor, S/P pituitary irradiation Cryptorchidism, S/P right orchiectomy Congenital hypogonadatropic hypogonadism Head trauma Left testicular trauma, S/P right orchiectomy
Normal range6
Serum T (nmol/L)a 4.0
Vol. 70, No. 3 Printed in U.S.A.
Testosterone Replacement Therapy and Sleep-Related Erections in Hypogonadal Men GLENN R. CUNNINGHAM, MAX HIRSHKOWITZ, STANLEY G. KORENMAN, AND ISMET KARACAN Medical (G.R.C.), Research (G.R.C., MM.), and Psychiatry (I.K.) Services, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas 77030; the Medical Service, Veterans Affairs Medical Center (S.G.K.), Sepulvada, California 91343; and University of California (S.G.K.), Los Angeles, California 90024
ABSTRACT. Hypogonadal men usually have diminished libido and erectile dysfunction, and testosterone replacement therapy in these men increases sexual activity, erotic thoughts, and self-reported nocturnal erections. The polygraphlc assessment of nocturnal penile tumescence (NPT) provides an objective index of erectile capability and is useful for differentiating psychogenic from organic erectile dysfunction. In this study we evaluated NPT in six hypogonadal adult men during and after termination of androgen therapy. Multinight sleep studies were conducted within 1 week and 7-8 weeks after each man received 200 mg testosterone cypionate, im. The mean serum testosterone level 4-7 days after testosterone injection was 35.9 ± 3.4 (±SE) nmol/L, and it fell to 2.3 ± 0.9 nmol/L after 7-8 weeks. Signif-
icant declines (P < 0.05) in the number of NPT episodes (3.7 to 2.0), maximum penile circumference increase (24 to 13 mm), and total tumescence time (107 to 55 min) accompanied the fall in the serum testosterone level. No androgen-related changes in the amount or integrity of rapid eye movement sleep were found. Finally, the mean penile rigidity (buckling pressure) decreased from 770 ± 98 to 590 ± 81 g (P < 0.05). Comparison of these results to those in normal men revealed that none of these men met all diagnostic criteria for organic impotence, even 7-8 weeks after discontinuation of testosterone administration. While men with androgen deficiency may have normal NPT, sleep-related erections increase in response to testosterone administration. (J Clin Endocrinol Metab 70: 792, 1990)
H
and free testosterone levels, but no relationship between NPT and serum FSH, LH, sex-hormone binding globulin, or PRL concentrations. Few studies have evaluated changes in sleep-related erections during testosterone therapy in hypogonadal men. In a study of six hypogonadal men, using portable home NPT monitors, administration of 200 mg testosterone enanthate, im, prolonged the time that the increase in penile circumference exceeded 15 mm (10). In another report, four hypogonadal men were studied before and during daily treatment with up to 160 mg testosterone undecanoate, orally, (11). Treatment increased penile circumference and total tumescence time and reduced the latency period before the first erection. The number of NPT episodes, however, did not change. Since measurement of NPT in hypogonadal men has been limited, we undertook this study to determine the relationship between androgen replacement therapy and changes in sleep-related erections. Laboratory polysomnography was used to avoid problems associated with home monitoring devices (12,13), and multinight recordings with erectile measures derived from both the penile base and tip (at the coronal sulcus) were made. Since penile rigidity is a critical measure of erectile activity (14-16), it also was assessed.
YPOGONADISM in men usually results in loss of both libido and potency (1), which can be restored by adequate testosterone replacement therapy. Specifically, self-reported measures of libido, nocturnal erections, and potency increase when hypogonadal men are treated with testosterone enanthate (2, 3) and testosterone undecanoate (4). However, objective documentation of such improvement is limited. Measurements of nocturnal penile tumescence (NPT) provide an objective and quantitative method for evaluating changes in erectile pattern. Furthermore, assessment of NPT is useful for the differentiation of organic from psychogenic erectile dysfunction (5-7). In a study of 172 men with complaints of erectile dysfunction and no history of testicular disease, 6 were identified as androgen deficient; all 6 had diminished NPT (8). Fenwick and co-workers (9) evaluated NPT and serum testosterone levels in 10 men with chronic epilepsy, 5 of whom had low-normal serum testosterone levels. They found positive correlations between NPT and serum total Received November 7, 1989. Address all correspondence and requests for reprints to: Glenn R. Cunningham, M.D., Veterans Administration Medical Center-lllE, 2002 Holcombe Boulevard, Houston, Texas 77030.
792
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 07 September 2014. at 17:18 For personal use only. No other uses without permission. . All rights reserved.
TESTOSTERONE AND SLEEP-RELATED ERECTIONS
Materials and Methods Patients Six hypogonadal men, aged 33-56 yr, were studied at the Baylor Sleep Disorders and Research Center (see Table 1). These men had received 200 mg testosterone cypionate, im, every 2-4 weeks for 3-18 yr before the study. All men reported normal and satisfactory sexual activity while receiving androgen replacement. The protocol was approved by the institutional review board, and each man gave written and oral informed consent. Procedures The first study period began 1-4 days after a man received 200 mg testosterone cypionate, im. The second study period was conducted 7-8 weeks later, with there having been no interim androgen replacement. By this time all men had been androgen deficient for at least 1 month. During the week before the second study period, the men wore a scrotal patch which contained no medication but was of the same design as those patches that do contain testosterone. The men were told that some patches would not contain testosterone and others would contain varied amounts of testosterone. During each study period the men were evaluated in the sleep laboratory for 3 consecutive nights. The first night of each session was used to acclimate (or reacclimate) the men to the laboratory. Sleep stages were scored from electroencephalographic, electrooculographic, and submental electromyographic tracings according to standard techniques (17) in which each minute of the record was classified as awake (stage 0), sleep stage 1,2,3, 4, or rapid eye movement (REM). Respiratory pattern was recorded with an abdominal strain gauge to measure diaphragmatic movement and a nasal-nasal/oral temperature sensor to measure air flow. Heart rate was recorded using precordial electrodes. NPT was assessed concurrently by measuring changes in penile circumference with strain gauges (mercury-filled rubber tubing) placed around the base and at the
793
coronal sulcus (tip) of the penis. A NPT episode was defined as a period during which the circumference at the base or tip increased by 2 mm or greater for 20 or more s [see Karacan (14) for details on standardized NPT scoring]. This scoring system avoids errors of omission when incomplete or partial tumescence episodes occur. Total tumescence time is the total time with tumescence for the night. All recordings were made using Grass model 78 polygraphs (Grass Instrument Co., Quincey, Houston, TX). NPT was recorded using AMS (American Medical Systems, Houston, TX) and TME (Texas Medical Electronics, Houston, TX)) NPT monitors interfaced to the polygraph. On one or more of the sleep-recording nights, the men were awakened during an episode of tumescence for measurement of penile rigidity (buckling force). In this procedure, force is applied to the tip of the penis and the pressure (measured in grams) required to bend the penile shaft 30° is determined. A penile rigidity of 500 g or greater has been empirically estimated as the minimum rigidity needed for vaginal intercourse (18). During the third night blood samples were obtained throughout the night by a constant withdrawal of blood from a forearm iv catheter. The samples were collected for 20-min intervals. Serum total and bloavailable testosterone, dihydrotestosterone, and estradiol concentrations were measured by RIA in the three samples collected 1, 3, and 5 h after bedtime (19-21). The bioavailable hormone concentration was measured by addition of [3H]testosterone, [3H]dihydrotestosterone, or [3H]estradiol and precipitation of the hormone-sex hormone-binding globulin complex with ammonium sulfate. The total hormone concentration was multiplied by the fraction of labeled hormone not precipitated to give the bioavailable concentration. Hormonal measurements were performed in the laboratory of Dr. S. G. Korenman. All samples from an individual man were analyzed in duplicate in the same assay. The intraassay variability for each of these assays was less than 6%, and the interassay variability was less than 8%. Sleep parameters and data analysis The sleep efficiency index (SEI) was calculated for each man for each night. It is the ratio of total sleep time to time in bed,
TABLE 1. Clinical characteristics of the six hypogonadal men Patient no.
Age (yrs)
1 2
33 36
3
37
4
34
5 6
56 53
Diagnosis Klinefelter's syndrome Pituitary tumor, S/P pituitary irradiation Cryptorchidism, S/P right orchiectomy Congenital hypogonadatropic hypogonadism Head trauma Left testicular trauma, S/P right orchiectomy
Normal range6
Serum T (nmol/L)a 4.0
