help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Luboshitzky, R.
Right arrow Articles by Herer, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Luboshitzky, R.
Right arrow Articles by Herer, P.
The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3160-3166
Copyright © 2003 by The Endocrine Society

Middle-Aged Men Secrete Less Testosterone at Night Than Young Healthy Men

Rafael Luboshitzky, Zila Shen-Orr and Paula Herer

Endocrine Institute, Haemek Medical Center (R.L.), Afula 18101, Israel; and Endocrine Laboratory, Rambam Medical Center (Z.S.-O.), and Sleep Research Center, Technion, Israel Institute of Technology (P.H.), Haifa 32000, Israel

Address all correspondence and requests for reprints to: Prof. R. Luboshitzky, Endocrine Institute, Hemeek Medical Center, Afula 18101, Israel. E-mail: luboshitzky_r{at}clalit.org.il.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Aging men largely maintain their testicular androgen production. Cross-sectional studies have demonstrated that after the age of 40 yr a 0.2–2% annual decline is observed in morning total testosterone. In elderly males, the coordinate release of LH and testosterone became asynchronous despite normal serum levels of these hormones.

The aim of this study was to test the reproductive hormone rhythm at night in middle-aged men. We studied seven healthy middle-aged (46.6 ± 6.7 yr) and six healthy young (23.9 ± 2.4 yr) men by determining their serum levels of LH and testosterone levels every 15 min from 1900–0700 h with simultaneous sleep recordings. The nocturnal rise in testosterone occurred earlier in young men (2235 ± 0022 h) and at 2331 ± 0057 h in middle-aged men (P < 0.04). In young men, the mean testosterone level at night (5.0 ± 1.3 ng/ml; 17.4 ± 4.4 nmol/liter) and the integrated nocturnal secretion [area under the curve (AUC); 60.6 ± 8.9 ng/ml·h; 210 ± 31 nmol/liter·h] were significantly higher compared with the values (3.6 ± 1.1 and 31.1 ± 7.2 ng/ml·h; 12.6 ± 3.8 and 108 ± 24.8 nmol/liter·h, respectively) observed in middle-aged men (P < 0.04 and P < 0.01, respectively). The mean (3.5 ± 0.3 mIU/ml; 3.5 ± 0.3 IU/liter) and AUC (43.4 ± 8.3 mIU/ml·h; 43.4 ± 8.3 IU/liter·h) LH values in middle-aged men were significantly higher than the values observed in young men (2.0 ± 0.7 and 30.8 ± 6.1 mIU/ml·h; 2.0 ± 0.7 and 30.8 ± 6.1 IU/liter·h; P < 0.05 and P < 0.01, respectively). Young men had significantly more testosterone pulses at night (6.7 ± 1.6/12 vs. 3.8 ± 1.1/12 h in middle-aged men; P < 0.005) of shorter interpulse interval (88.5 ± 23.6 vs. 137.4 ± 46.4 min; P < 0.02). LH pulse characteristics and sleep quality were similar in both groups. However, the first rapid eye movement (REM) sleep episode occurred earlier in middle-aged men (2303 ± 0034 h) vs. young men (0010 ± 0054 h; P < 0.04). As a consequence, the testosterone rise antedated the first REM episode by 90 min in young men. The link between testosterone rise and REM sleep episode was not observed in middle-aged men. Linear regression analysis revealed that the LH AUC was significantly related to age (P < 0.02). Analysis of covariance revealed that the two groups differed significantly in testosterone AUC (P < 0.04).

Comparison of LH and testosterone concentrations showed significant and positive cross-correlations between LH and testosterone only in young men, with the testosterone rise lagging 60 min after the rise in LH. Our findings suggest that in middle-aged men, less pulsatile testosterone and more LH are secreted at night than in young men, with disruption of the association between testosterone rhythm and REM sleep. The decline in nocturnal testosterone secretion appears to involve a combination of testicular and pituitary hypogonadism.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN YOUNG ADULT males testosterone is secreted in an episodic fashion in response to an LH stimulus (1). An overall diurnal rhythm is seen for testosterone, which is maximal in the early morning hours and minimal in the evening (2). The nocturnal testosterone rhythm is related to deep sleep (3) and to rapid eye movement (REM)/non-REM sleep cycles (4). Peaks in testosterone coincide with the onset of REM sleep (5). In young men the sleep-related testosterone rise is linked with the appearance of the first REM sleep episode (6).

Androgen production declines with age in men, resulting in decreased serum levels of both total and bioavailable testosterone (7). The circadian rhythmicity in serum testosterone levels found in young men was attenuated, and the mean 24-h testosterone levels were lower in elderly men (8). The pathophysiological mechanisms underlying this hypoandrogenemia are not known. Several cross-sectional studies measuring fasting morning hormone levels have revealed that testosterone and dehydroepiandrosterone sulfate undergo a gradual decline after the age of 40 yr, associated with increases in LH, FSH, and SHBG levels (9, 10, 11, 12). Older men exhibit blunted peak serum testosterone levels in response to human chorionic gonadotropin stimulation (13). Also, the administration of recombinant human LH after an LH-down-regulating dose of leuprolide acetate revealed that older men had delayed initial and reduced maximal serum testosterone levels compared with young men (13). These data suggested primary testicular failure. In middle-aged men the mean and integrated LH values did not differ from those observed in young men, although LH pulse frequency increased, suggesting relative hypogonadotropic hypogonadism (14).

Recent studies have reported that a decline in deep sleep already occurs in middle-aged men (15). We have demonstrated that in young men, the sleep-related rise in serum testosterone levels is linked with the appearance of the first REM sleep. Fragmented sleep disrupted the testosterone rhythm, with attenuation of the nocturnal rise in men who did not experience REM sleep. These findings suggested that a single circadian oscillator that controls REM sleep, core body temperature, and melatonin is related to LH-testosterone secretion (6). In older men decreases in sleep efficiency and number of REM episodes and an increase in REM latency were associated with lower testosterone levels (4). Others have suggested that the interactive coupling between reproductive axis, brain sleep-wake cycles, and neural nocturnal penile tumescence oscillations are disrupted in aging men (3).

As many differences in LH and testosterone secretory patterns have been described with aging, the present study was undertaken to determine the dynamics of nocturnal LH and testosterone secretion in middle-aged men and to examine whether changes in sleep with aging are related to changes in the secretion of these hormones. To address these issues we analyzed nocturnal pulsatile serum LH and testosterone levels, obtained at 15-min intervals, with simultaneous sleep recordings.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Participants

Seven healthy middle-aged (46.6 ± 6.7 yr) and six healthy young (23.9 ± 2.4 yr) men volunteered to participate in the study. All were in good health, nonsmoking, and nonobese and received no medications. The study was approved by the Helsinki Committee of the Afula Medical Center (Afula, Israel). All participants gave their informed consent before the onset of the study.

Study protocol

Subjects were admitted to the Sleep Research Center at 1800 h. They slept between 2200 and 0700 h for habituation, with electrodes attached for sleep recordings. During the experimental night, at 1800 h, an iv catheter was inserted into an antecubital vein, kept patent by a slow infusion of 0.9% NaCl. Blood samples (3 ml) were collected every 15 min from 1900–0700 h. Between 2200–0700 h lights were off, and subjects remained in bed and attempted to fall asleep. Polysomnographic sleep recordings were conducted between 2200–0700 h.

Analysis of sleep stages

Electrodes were attached for the following electrophysiological recordings: two electroencephalograms (C3-A2 and C4-A1), two electrooculograms, and one electromyogram of the mentalis. Sleep stages were recorded in 30-sec epochs using conventional methods (16). The following parameters were determined: total recording time, real sleep time (total recording time - sleep latency - waking periods), sleep latency (time from lights off until 3 consecutive min of stage 2), sleep efficiency (real sleep time/total recording time), REM latency (time to first REM), first REM sleep episode (time from beginning of sleep to the first REM episode).

Hormone measurements

Blood was centrifuged, immediately separated, and stored at 22 C until assayed. Serum LH and testosterone levels were determined in each sample in duplicate using an immunoradiometric technique (Biodata Diagnostics, Rome, Italy). The intraassay coefficients of variation (CV) were 6.0% and 3.0% for low (0.6–1.1 ng/ml; 2.2–4.0 nmol/liter) and high (8.5–17.9 ng/ml; 29.4–62.0 nmol/liter) testosterone concentrations, respectively. The interassay CV were 1.9% and 1.6%, respectively. The sensitivity of the assay was 0.04 ng/ml (0.15 nmol/liter). The LH intraassay CV were 2.1% and 3.2% for low (2.2–3.3 m IU/ml; 2.2–3.3 IU/liter) and high (27–41 mIU/ml; 27–41 IU/liter) concentrations, respectively. The interassay CV were 3.7% and 0.8%, respectively. The sensitivity of the assay was 0.15 mIU/ml (0.15 IU/liter).

Statistical analysis

Mean and integrated [area under the curve (AUC)] serum LH and testosterone levels from 1900–0700 h were determined in the two groups. The onset of the testosterone rise was defined as the time of the first occurrence of at least three consecutive samples exceeding the mean levels obtained between 1900 and 2200 h by more than 1 SD. Significant LH and testosterone secretory pulses were identified using the pulse detection program ULTRA (17). The general principle of this algorithm is the elimination of all peaks for which either the increment (difference between the peak and the preceding trough) or the decrement (difference between the peak and the next trough) does not exceed a certain threshold related to measurement error. The SD of the error associated with each calculated secretory rate was calculated following the theory of error propagation, assuming normally distributed errors on plasma levels. For each significant pulse, the amplitude was defined as the difference between the level at the peak and the level at the preceding trough. We determined the number and interpulse interval of LH and testosterone pulses, the absolute increment of the pulse and the half-life, using a threshold of 2 CVs. Independent two-sample t tests were used to compare the mean LH and testosterone levels, the AUC, the 0700 h testosterone level, pulse characteristics, and sleep data between the two groups. A repeated measure ANOVA was performed to test the difference between the two age groups’ mean hourly LH and testosterone levels. The relationship between age and the mean LH and testosterone concentrations as well as LH and testosterone AUC were analyzed by linear regression. Analysis of covariance, using mean LH or LH AUC as the covariate, was used to examine the relationship between age group and the mean and AUC of testosterone. Cross-correlation analysis was used to measure the strength of the tendency of LH and testosterone to vary in the same or opposite directions over time. Pearson correlation (r) was computed over 12 lag units, with the higher absolute value of r taken to be the lag time. The lag time and correlations of the two groups were compared by two independent sample t and z tests.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Sleep quality and sleep stage data were similar in middle-aged and young men (Table 1Go). All participants had REM sleep episodes during the experimental night. The first REM sleep episode was observed at 0010 ± 0054 h in young men compared with 2303 ± 0034 h in middle-aged men (P < 0.04). All subjects had a well defined nocturnal testosterone rise (Table 2Go). In young men the testosterone onset antedated the appearance of the first REM sleep episode by 95 min. In middle-aged men, no association was observed between the nocturnal rise in testosterone and the appearance of the first REM sleep. The middle-aged men had significantly higher mean and AUC LH values compared with young men (Table 2Go and Fig. 1Go). The mean nocturnal and 0700 h testosterone levels were significantly higher in young men compared with middle-aged men. The testosterone AUC in young men (60.6 ± 8.9 ng/ml·h; 210 ± 31 nmol/liter·h) was significantly higher than that in middle-aged men (31.2 ± 7.2 ng/ml·h; 108 ± 24.8 nmol/liter·h; P < 0.01). As shown in Table 3Go, young men had significantly more testosterone pulses (6.7 ± 1.6 pulses/12 h) than middle aged men (3.8 ± 1.1 pulses/12 h; P < 0.005) of shorter interpulse interval (88.5 ± 23.6 vs. 137.4 ± 46.6 min, respectively; P < 0.05). The two groups had similar numbers of LH pulses of similar interpulse intervals. The ratio between the number of LH and testosterone pulses was 0.9 in young men compared with 1.4 in middle-aged men. Individual nocturnal profiles of LH and testosterone secretory rates in young and middle-aged men are shown in Fig. 2Go.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Characteristics of nocturnal (2200–0700 h) sleep quality data in middle aged and young healthy men

 

View this table:
[in this window]
[in a new window]
  		TABLE 2. Pituitary-gonadal hormones status in middle aged and young healthy men

 


View larger version (35K):
[in this window]
[in a new window]
  		FIG. 1. Nocturnal LH and testosterone secretion in middle-aged and young healthy men. An arrow indicates the first REM sleep episode. Between 2200–0700 h, lights were off, and subjects were asleep. To convert testosterone units to nanograms per milliliter, divide by 3.467. To convert LH units to milliinternational units per milliliter, divide by 1.

 

View this table:
[in this window]
[in a new window]
  		TABLE 3. Characteristics of pulsatile LH and testosterone nocturnal secretion in middle aged and young healthy men

 


View larger version (33K):
[in this window]
[in a new window]
  		FIG. 2. Individual nocturnal profiles of LH and testosterone secretory rates in young men (left) and middle-aged men (right). Asterisks denote a significant pulse of secretion. To convert testosterone units to nanograms per milliliter, divide by 3.467. To convert LH units to milliinternational units per milliliter, divide by 1.

 
Repeated measures analysis of testosterone levels revealed that there was a time effect (F = 15.48; P < 0.001) and an interaction between time and age group (F = 3.02; P < 0.001). Post hoc testing (Duncan’s multiple range test) of the time effect revealed that testosterone levels were lower before 2300 h than after 2300 h. Bonferroni post hoc test revealed that young men had higher testosterone levels than middle-aged men (t = 1.86; P < 0.04). Repeated measures analysis of LH levels revealed a time effect (F = 1.86; P < 0.05). Bonferroni post hoc test revealed that middle-aged men had higher LH levels than young men (t = 2.26; P < 0.02). Analysis of covariance, using LH AUC as a covariate, revealed that there was a statistically significant difference between the two age groups in testosterone AUC (P < 0.04). Cross-correlation analysis revealed that an increase in testosterone concentration occurred 50.0 ± 18.2 min before a rise in LH concentration in young men and 127.5 ± 84.7 min before the LH rise in middle-aged men (Fig. 3Go). This was a statistically significant difference (P < 0.05). Middle-aged men had lag times of 30–240 min, whereas young men had lag times of 15–60 min. No positive correlation was found in one middle-aged man. There was no statistically significant difference in the strength of the correlation (r = 0.49 in young men and r = 0.26 in middle-aged men; P > 0.50). A comparison of LH and testosterone concentrations in young men showed significant and positive cross-correlations between LH and testosterone when the later lagged by 9–96 min. In fact, LH and testosterone were positively correlated, with the testosterone rise lagging 60 min after the rise in LH. No extended positive cross-correlations between LH and testosterone were found in middle-aged men.



View larger version (17K):
[in this window]
[in a new window]
  		FIG. 3. Cross-correlation between testosterone and LH in middle-aged (A) and young (B) men. A positive lag means lagged LH, and a negative lag means lagged testosterone. The dots show the cross-correlation for each individual. The solid line is an average for the population. The dotted lines define the range outside which correlations are significantly at the 5% level.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study we demonstrated that in middle-aged men less pulsatile testosterone and more LH are secreted at night, with disruption of the association between testosterone rise and the appearance of first REM sleep. Cross-correlation analysis revealed a significant positive correlation between LH and testosterone only in young men, with the testosterone rise lagging 60 min after the rise in LH. The diminution in testosterone secretion seen in middle-aged men combined with a compensatory increase in LH levels and the asynchrony between LH and testosterone observed in our study may suggest relative testicular and pituitary hypogonadism. Over the last 15 yr several studies have investigated the nocturnal LH-testosterone rhythms in elderly men by measuring serum hormone levels over a 24-h period. Frequent sampling (every 10 min) studies revealed reduced serum testosterone concentrations with decreases in LH and testosterone pulse frequency (13). Intense sampling (every 2.5 min) over a period of 7 h disclosed normal mean LH and testosterone levels, but increased LH pulse frequency and reduced testosterone secretory bursts (3). In agreement with our findings, these studies suggested that reduced testosterone secretion in elderly men results from both pituitary and testicular defects. However, in these reports the association between LH-testosterone secretion and sleep patterns was not studied.

In healthy elderly men a blunted testosterone response to human chorionic gonadotropin together with an elevation of basal LH levels indicated a defect in Leydig cell steroidogenesis (18, 19). Low testicular volume was described in elderly men and was associated with a decrease in inhibin B/FSH and testosterone/LH ratios, suggesting a combined Leydig cell and Sertoli cell dysfunction (20). On the other hand, Korenman et al. (21) have suggested that almost all elderly men with reduced testosterone levels have evidence of hypothalamic-pituitary dysfunction, as reflected by low basal LH levels and blunted LH response to GnRH stimulation. Pulsatile LH release in elderly men is marked by lower amplitude and more frequent secretory events (22). GnRH infusion for 2 wk in elderly men restored LH pulsatile values to levels achieved in young men. The synchrony between LH and testosterone secretion is disrupted in the elderly, suggesting an impaired output of the GnRH-LH axis (14).

Age-related changes in sleep quality were nonconclusive, as sleep stages were similar in middle-aged and elderly subjects and between young and elderly subjects (23), whereas others reported that older men spent more time awake and displayed decreased REM latency (24). Among the most common sleep changes detected in middle-aged subjects are decreased sleep stages 3 and 4 (deep sleep) and increased number and duration of nocturnal awakening. In our study middle-aged men tended to have more awakening periods and less sleep stages 3 and 4, although this was not statistically significantly different from young men. The effect of aging on REM sleep is variable and occurs later in life. This may be due to the fact that REM sleep is regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (25, 26). It was assumed that LH-testosterone rhythms are dependent on specific phase relationship between sleep and the underlying circadian oscillator rather than on the circadian oscillator per se (27). In young men the first REM period appears after 90 min of non-REM sleep. The characteristics of the REM/non-REM cycle during sleep were shown to be age dependent (28).

Aging in men is associated with decreases in bone mineral density and muscle mass and strength and an increase in adiposity (29, 30, 31, 32). The age-associated decline in testosterone levels was linked with abdominal obesity and insulin resistance (33, 34). Epidemiological studies have demonstrated higher cardiovascular risks in men with lower testosterone levels (35, 36). Over the last decade several clinical studies have been undertaken to determine whether testosterone supplementation in aging is beneficial. Significant improvement in bone mineral density, muscle mass and strength, plasma lipids, and insulin sensitivity was observed only in elderly men with subnormal testosterone levels (29, 37). Other studies failed to demonstrate changes in serum lipids during testosterone treatment (31). It is not yet clear whether androgen supplementation affects cardiovascular morbidity and mortality (30). The increased prevalence of metabolic syndrome (obesity, insulin resistance, dyslipidemia, and hypertension) and consequently cardiovascular disease is frequently observed in middle-aged men (38). The associated decline in nocturnal testosterone secretion in a similar age group observed in the present study suggests that testosterone treatment is indicated in middle-aged men to determine whether its supplementation is beneficial.

In conclusion, middle-aged men secrete less testosterone and more LH at night than young healthy men. The synchrony between LH and testosterone and the link between the nocturnal rise in testosterone and the appearance of the first REM sleep episode are disrupted. These findings suggest that hypoandrogenemia in middle-aged men results from combined testicular, pituitary, and central nervous system dysfunctions.


   Footnotes
 
Abbreviations: AUC, Area under the curve; BMI, body mass index; CV, coefficient of variation; REM, rapid eye movement.

Received December 5, 2002.

Accepted April 4, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Foresta C, Bordon P, Rossato M, Mioni R, Velduis JD 1997 Specific linkages among luteinizing hormone, follicle-stimulating hormone, and testosterone release in the peripheral blood and human spermatic vein. Evidence of both positive (feed forward) and negative (feedback) within axis regulation. J Clin Endocrinol Metab 82:3040–3046[Abstract/Free Full Text]
  2. Plymate SR, Tenover JS, Bremner WJ 1989 Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men. J Androl 10:366–371[Abstract/Free Full Text]
  3. Veldhuis JD, Iranmanesh A, Godschalk M, Mulligan T 2000 Older men manifest multifold synchrony disruption of reproductive neurohormone outflow. J Clin Endocrinol Metab 85:1477–1486[Abstract/Free Full Text]
  4. Schiavi RC, White D, Mandeli J 1992 Pituitary-gonadal function during sleep in healthy aging men. Psychoneuroendocrinology 17:599–609[CrossRef][Medline]
  5. Hishkowitz M, Moore CA, O’Connor S, Beallamy M, Cunningham GR 1997 Androgen and sleep related erections. J Psychosomat Res 42:541–546[CrossRef][Medline]
  6. Luboshitzky R, Zabari Z, Shen-Orr Z, Herer P, Lavie P 2001 Disruption of the nocturnal testosterone rhythm by sleep fragmentation in normal men. J Clin Endocrinol Metab 86:1134–1139[Abstract/Free Full Text]
  7. Gray A, Feldman HA, McKinlay JB, Longcope C 1991 Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 73:1016–1025[Abstract]
  8. Bremner WJ, Vitiello MV, Prinz PN 1983 Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab 56:1278–1281[Abstract]
  9. Simon D, Preziosi P, Barett-Connor E, Roger M, Saint-Paul M, Nah K, Papoz L 1992 The influence of aging on plasma sex hormones in men. Am J Epidemiol 135:783–791[Abstract/Free Full Text]
  10. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR 2001 Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 86:724–731[Abstract/Free Full Text]
  11. Hsieh CC, Sigmorello LB, Lipworth L, Lagion P, Mantzonos CS, Trichopoulos D 1998 Predictors of sex hormone levels among the elderly: a study in Greece. J Clin Epidemiol 51:837–841[CrossRef][Medline]
  12. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB 2002 Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 87:589–598[Abstract/Free Full Text]
  13. Mulligan T, Iranmanesh A, Veldhuis ID 2001 Pulsatile iv infusion of recombinant human LH in leuprolide-suppressed men unmasks impoverished Leydig-cell secretory responsiveness to midphysiological LH drive in the aging male. J Clin Endocrinol Metab 86:5547–5553[Abstract/Free Full Text]
  14. Veldhuis JD, Urban RJ, Lizarralde G, Johnson MI, Iranmanesh A 1992 Attenuation of luteinizing hormone secretory burst amplitude as a proximate basis for the hypoandrogenism of healthy aging in men. J Clin Endocrinol Metab 75:707–713[Abstract]
  15. Vgontzas AN, Bixler EO, Wittman AM, Zachman K, Lin HM, Vela-Bueno A, Kales A, Chrousos GP 2001 Middle-aged men show higher sensitivity of sleep to the arousing effects of corticotropin-releasing hormone than young men: clinical implications. J Clin Endocrinol Metab 86:1489–1495[Abstract/Free Full Text]
  16. Rechtschffen A, Kales A 1968 A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington DC: U.S. Government Printing Office; NIH Publication 204
  17. Spiegel K, Leproult R, Colecchia EF, L’Hermite-Baleriaux M, Nie Z, Copinschi G, Van Cauter E 2000 Adaptation of the 24-h growth hormone profile to a state of sleep debt. Am J Physiol 279:R874–R883
  18. Nunkin HR, Lin T, Murono EP 1981 The aging Leydig cell. III. Gonadotropin stimulation in men. J Androl 2:181–186[Abstract]
  19. Harman SM, Tsitouras PD 1980 Reproductive hormones in aging men. I. Measurement of sex steroids, basal luteinizing hormone, and Leydig cell response to human chorionic gonadotropin. J Clin Endocrinol Metab 51:35–40[Abstract]
  20. Mahmoud AM, Goemaere S, El-Garem Y, VanPottelbergh I, Comhaire FH, Kaufman JM 2003 Testicular volume in relation to hormonal indices of gonadal function in community-dwelling elderly men. J Clin Endocrinol Metab 88:179–184[Abstract/Free Full Text]
  21. Korenman SG, Morley JE, Mooradian AD, Davis SS, Kaiser FE, Silver AJ, Viosca SP, Garza D 1990 Secondary hypogonadism in older men: its relation to impotence. J Clin Endocrinol Metab 71:963–969[Abstract]
  22. Keenan DM, Veldhuis JD 2001 Hypothesis testing of the aging male gonadal axis via a biomathematical construct. Am J Physiol 280:R1755–R1771
  23. Murphy PJ, Rogers NL, Campbell SC 2000 Age difference in the spontaneous termination of sleep. J Sleep Res 9:27–34[CrossRef][Medline]
  24. Ehlers CL, Kupfer DJ 1989 Effects of age on delta and REM sleep parameters. Electroencephalogr Clin Neurophysiol 72:118–125[CrossRef][Medline]
  25. Blackman MR 2000 Age-related alterations in sleep quality and neuroendocrine function. JAMA 284:879–891[Free Full Text]
  26. Van Cauter E, LeProult R, Plat L 2000 Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and Cortisol levels in healthy men. JAMA 284:861–868[Abstract/Free Full Text]
  27. Luboshitzky R, Aviv A, Hefetz A, Herer P, Shen-Orr Z, Lavie L, Lavie P 2002 Decreased pituitary-gonadal secretion in men with obstructive sleep apnea. J Clin Endocrinol Metab 87:3394–3398[Abstract/Free Full Text]
  28. Lavie P 2001 Sleep-wake as a biological rhythm. Ann Rev Psychol 52:277–303[CrossRef][Medline]
  29. Tenover JS 1992 Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 75:1092–1098[Abstract]
  30. Vermeulen A 2001 Androgen replacement therapy in the aging male: a critical evaluation. J Clin Endocrinol Metab 86:2380–2390[Free Full Text]
  31. Kunelius P, Lukkarinen O, Hannuksela ML, Itkonen O, Tapanainen JS 2002 The effects of transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study. J Clin Endocrinol Metab 87:1467–1472[Abstract/Free Full Text]
  32. Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ 2003 Differential anabolic effects of testosterone and amino acid feeding in older men. J Clin Endocrinol Metab 88:358–362[Abstract/Free Full Text]
  33. Abate N, Haffner SM, Garg A, Peshock RM, Grundy SM 2002 Sex steroid hormones, upper body obesity, and insulin resistance. J Clin Endocrinol Metab 87:4522–4527[Abstract/Free Full Text]
  34. Couillard C, Gagnon J, Bergeron J, Leon AS, Rao DC, Skinner JS, Wilmore JH, Despres JP, Bouchard C 2000 Contribution of body fatness and adipose tissue distribution to the age variation in plasma steroid hormone concentrations in men: the HERITAGE family study. J Clin Endocrinol Metab 85:1026–1031[Abstract/Free Full Text]
  35. Hak AE, Witteman JCM, de Jong FH, Geerlings MI, Hofman A, Pols HAP 2002 Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: The Rotterdam Study. J Clin Endocrinol Metab 87:3632–3639[Abstract/Free Full Text]
  36. Alexanderson P, Haarbo J, Christiansen C 1996 The relationship of natural androgens to coronary heart disease in males. Atherosclerosis 125:1–13[CrossRef][Medline]
  37. Snyder PJ 2001 Effects of age on testicular function and consequences of testosterone treatment. J Clin Endocrinol Metab 86:2369–2372[Free Full Text]
  38. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT 2002 The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
F. Joseph, B. Y. Chan, B. H. Durham, A. M. Ahmad, S. Vinjamuri, J. A. Gallagher, J. P. Vora, and W. D. Fraser
The Circadian Rhythm of Osteoprotegerin and Its Association with Parathyroid Hormone Secretion
J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3230 - 3238.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
J. Axelsson, M. Ingre, T. Akerstedt, and U. Holmback
Effects of Acutely Displaced Sleep on Testosterone
J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4530 - 4535.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
A. G Zabka, G. S Mitchell, and M Behan
Ageing and gonadectomy have similar effects on hypoglossal long-term facilitation in male Fischer rats
J. Physiol., March 1, 2005; 563(2): 557 - 568.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
W. de Ronde, A. Hofman, H. A P Pols, and F. H de Jong
A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women
Eur. J. Endocrinol., February 1, 2005; 152(2): 261 - 268.
[Abstract] [Full Text] [PDF]

Home page
 J AndrolHome page
A. Lerchl and R. Luboshitzky
Melatonin Administration Alters Semen Quality in Normal Men
J Androl, March 1, 2004; 25(2): 185 - 187.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Luboshitzky, R.
Right arrow Articles by Herer, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Luboshitzky, R.
Right arrow Articles by Herer, P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals