The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: response to clomiphene citrate

Serum testosterone (T) levels in men decline with age while serum LH levels, as measured by RIA, increase. To assess if the decline in serum T levels in healthy aging men is paralleled by an age-related decline in the bioavailable non-sex hormone-binding globulin (SHBG)-bound fraction of T and to determine whether there are age-related changes in LH secretion or LH control of T production, we studied 29 young (aged 22-35 yr) and 26 elderly (aged 65-84 yr) healthy men. All men had single random blood samples drawn, and 14 men in each age group underwent frequent blood sampling for 24 h, both before and after 7 days of clomiphene citrate (CC) administration. Both mean 24-h serum total T levels and non-SHBG-bound T were reduced in elderly men compared to those in young men (P less than 0.05), while estradiol and SHBG levels were similar in the 2 age groups. Serum FSH determined by RIA and LH by RIA and bioassay were higher in the elderly men compared to those in young men (P less than 0.05), but the ratios of LH bioactivity to immunoreactivity and the LH pulse frequency and amplitude were similar. After CC administration, mean serum total T and non-SHBG-bound levels in young men increased by 100% and 304%, respectively, while in older men these values increased by only 32% and 8%, respectively. However, CC-stimulated LH pulse characteristics and serum levels of estradiol, SHBG, FSH, and bioactive and immunoreactive LH were similar in the 2 groups. Thus, both at baseline and after CC stimulation, elderly men had significantly lower serum total T and non-SHBG-bound (bioavailable) T levels than did young men, despite similar or increased levels of bioactive LH and similar bioactive to immunoreactive LH ratios and LH pulse characteristics. These results suggest that major age-related changes in the hypothalamic-pituitary-testicular axis occur at the level of the testes and are manifested by decreased responsiveness to bioactive LH. Administration of CC to young and elderly men resulted in similar changes in LH pulse characteristics and LH bioactivity and immunoreactivity, suggesting preserved hypothalamic-pituitary responsiveness in the elderly.     

Loss of circadian rhythmicity in blood testosterone levels with aging in normal men

Previous studies concerning the relationship of serum testosterone levels to aging in normal men have yielded apparently inconsistent results. Studies performing blood sampling in the morning have often shown an age-related decrease in testosterone levels, while those using afternoon samples have failed to show such a decrease. These results suggested to us the possibility that the circadian rhythm in serum testosterone levels might be altered with normal aging in men. Hourly blood samples were obtained for 24 h from 1 young (mean age, 52.2 yr) and 12 old (mean age, 17 yr) healthy men. Total testosterone levels were measured by RIA. The circadian rhythm in serum testosterone levels found in normal young men was markedly attenuated or absent in healthy elderly men; the early morning rise in testosterone levels characteristic of young men was not present in old age. Mean testosterone levels for the entire 24-h day were lower in healthy old men than in young men. These results demonstrate a clear decrease in serum testosterone levels in healthy old men compared to those in young men and provide an explanation for the inability to demonstrate an age-related decline in testosterone levels in earlier studies using serum samples obtained in the afternoon.     

Serum total and bioavailable testosterone levels, central obesity, and muscle strength changes with aging in healthy Chinese men

OBJECTIVES: To investigate the effects of the changes in serum bioavailable and total testosterone (TT) levels with aging on visceral body fat distribution and muscle strength in Chinese men.
DESIGN: Cross-sectional study.
SETTING: Ambulatory care.
PARTICIPANTS: Four hundred seventy-five healthy ambulatory Chinese men (aged 18–89, body mass index (BMI) 16.4–40.0 kg/m²).
MEASUREMENTS: Morning serum total and bioavailable testosterone levels, waist circumference (WC), waist-hip ratio (WHR), and right handgrip strength.
RESULTS: Mean serum TT levels fell mildly but significantly with aging ( P =.02, linear trend; one-way analysis of variance (ANOVA)), whereas mean serum bioavailable testosterone (BT) levels fell greatly with aging ( P <.001, linear trend, one-way ANOVA). The rates of decline in serum TT and BT levels were 0.2% and 1.14% per year, respectively. [Correction added after online publication 14-May-2008: BT levels have been corrected from 1.44% to 1.14%.] After adjustment for adiposity according to BMI, multiple linear regression analyses showed that age remained significantly related to serum TT and BT levels. Handgrip strength decreased with age (correlation coefficient ( r )=−0.394, P <.001) and was greater with higher serum BT levels ( r =0.239, P <.001) but not with higher TT levels. WHR, before and after adjustment for BMI, was inversely related to serum TT ( r =−0.34 and −0.197 respectively, P <.001) and BT levels ( r =−0.104, P <.05 and −0.161, P <.001, respectively).
CONCLUSION: In Chinese men, serum BT levels decreased with aging and may contribute to central obesity and poorer muscle strength in aging men.     

Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels

BACKGROUND: A large proportion of men over 65 years of age have bioavailable testosterone levels below the reference range of young adult men. The impact of this on musculoskeletal health and the potential for improvement in function in this group with testosterone supplementation require investigation. METHODS: Sixty-seven men (mean age 76 +/- 4 years, range 65--87) with bioavailable testosterone levels below 4.44 nmol/l (lower limit for adult normal range) were randomized to receive transdermal testosterone (two 2.5-mg patches per day) or placebo patches for 1 year. All men received 500 mg supplemental calcium and 400 IU vitamin D. Outcome measures included sex hormones (testosterone, bioavailable testosterone, sex-hormone binding globulin [SHBG], estradiol, and estrone), bone mineral density (BMD; femoral neck, Ward's triangle, trochanter, lumbar spine, and total body), bone turnover markers, lower extremity muscle strength, percent body fat, lean body mass, hemoglobin, hematocrit, prostate symptoms, and prostate specific antigen (PSA) levels. RESULTS: Twenty-three men (34%) withdrew from the study; 44 men completed the trial. In these men, bioavailable testosterone levels increased from 3.2 +/- 1.2 nmol/l (SD) to 5.6 +/- 3.5 nmol/l (p <.002) at 12 months in the testosterone group, whereas no change occurred in the control group. Although there was no change in estradiol levels in either group, estrone levels increased in the testosterone group (103 +/- 26 pmol/l to 117 +/- 33 pmol/l; p <.017). The testosterone group had a 0.3% gain in femoral neck BMD, whereas the control group lost 1.6% over 12 months (p =.015). No significant changes were seen in markers of bone turnover in either group. Improvements in muscle strength were seen in both groups at 12 months compared with baseline scores. Strength increased 38% (p =.017) in the testosterone group and 27% in the control group (p =.06), with no statistical difference between the groups. In the testosterone group, body fat decreased from 26.3 +/- 5.8% to 24.6 +/- 6.5% (p =.001), and lean body mass increased from 56.2 +/- 5.3 kg to 57.2 +/- 5.1 kg (p =.001), whereas body mass did not change. Men receiving testosterone had an increase in PSA from 2.0 +/- 1.4 microg/l to 2.6 +/- 1.8 microg/l (p =.04), whereas men receiving placebo had an increase in PSA from 1.9 +/- 1.0 microg/l to 2.2 +/- 1.5 microg/l (p =.09). No significant differences between groups were seen in hemoglobin, hematocrit, symptoms or signs of benign prostate hyperplasia, or PSA levels. CONCLUSIONS: Transdermal testosterone (5 mg/d) prevented bone loss at the femoral neck, decreased body fat, and increased lean body mass in a group of healthy men over age 65 with low bioavailable testosterone levels. In addition, both testosterone and placebo groups demonstrated gains in lower extremity muscle strength, possibly due to the beneficial effects of vitamin D. Testosterone did result in a modest increase in PSA levels but resulted in no change in signs or symptoms of prostate hyperplasia.     

Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels

BACKGROUND: Sex hormones are known to affect cholesterol levels and vascular tone in women. The effects of testosterone on cholesterol and vascular tone in men are less well understood. Low testosterone levels have been associated with higher cholesterol levels in epidemiologic studies, but testosterone replacement has resulted in variable changes in cholesterol levels. Similarly, clinical studies suggest that testosterone may be vasodilatory, but few studies have directly evaluated the effects of testosterone on vascular tone. METHODS: Sixty-seven men (mean age 76 +/- 4 years, range 65-87) with bioavailable testosterone levels below 4.44 nmol/l (lower limit for adult normal range) were randomized to receive transdermal testosterone (2-2.5 mg patches/d) or placebo patches for 1 year. Twenty-three men (34%) withdrew from the study; 44 men completed the trial. RESULTS: While total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels did not significantly change during the year of therapy, high-density lipoprotein (HDL) levels (p =.004) and, specifically, HDL(2) subfraction (p =.02) decreased in men receiving testosterone supplementation. Vascular tone was measured by brachial artery reactivity in 36 men. Endothelium-dependent brachial artery reactivity did not change from baseline measurements in men receiving transdermal testosterone (0.3 +/- 6.7% to 1.6 +/- 4.6%; p =.58) or in the placebo group (3.2 +/- 5.5% to 0.7 +/- 5.5%; p =.23). CONCLUSIONS: Transdermal testosterone decreased HDL(2) cholesterol but did not affect vascular reactivity in men older than 65 years selected for low testosterone levels. No study to date has addressed the direct relationship between testosterone replacement and cardiovascular events.     

Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels

BACKGROUND: Many men older than 50 years have bioavailable testosterone levels below the reference range for young adult men. The impact of the decreased androgen levels on cognition and health perception has received little attention. METHODS: Sixty-seven men (mean age 76 +/- 4 years, range 65-87) with bioavailable testosterone levels below 128 ng/dl (lower limit for adult normal range) were randomized to receive transdermal testosterone (2-2.5 mg patches/d) or placebo patches for 1 year. All men received 500 mg supplemental calcium and 400 IU vitamin D. Outcome measures included sex hormones [testosterone, bioavailable testosterone, sex hormone binding globulin (SHBG), estradiol, and estrone], cognitive tests (Digit Symbol, Digit Span, Trailmaking A and B), health perception (Medical Outcome Survey Short-form 36 or SF-36), lower extremity muscle strength and power, and calcium intake. RESULTS: Twenty-three men (34%) withdrew from the study; 44 men completed the trial. Bioavailable testosterone levels increased from 93 +/- 34 (SD) to 162 +/- 100 ng/dl (p <.002) at 12 months in the testosterone group (n = 24) while no change occurred in the control group (n = 20). While there was no change in estradiol levels in either group, estrone levels increased in the testosterone group (28 +/- 7 to 32 +/- 9 pg/dl, p =.017). Scores on the Digit Symbol test improved in both the testosterone and placebo groups. Scores on Trailmaking B improved in men treated with testosterone (p <.005), although the changes were not statistically different from the changes seen in the placebo group. Twelve-month scores on Trailmaking B for the entire group were correlated with 12-month testosterone levels (p =.016). Scores for health perception measured by SF-36 did not change significantly, though scores of mental and general health declined in both groups during the 12-month intervention. Twelve-month bioavailable testosterone scores were directly correlated with scores for physical role (p =.022), vitality (p =.036), and the physical composite score (p =.010). CONCLUSIONS: Transdermal testosterone treatment in men with low bioavailable testosterone levels does not impair and may improve cognitive function. Treatment did not improve health perception but this may have been due to the side effects of skin irritation suggested by similar reactions in both the testosterone and placebo groups.     

The relationship between libido and testosterone levels in aging men

CONTEXT: Although it is known that serum testosterone (T) concentrations are related to libido, the strength of that relationship in community-dwelling men has not yet been determined. OBJECTIVE: Our objective was to assess the strength and significance of the association between aging men's self-reports of libido and serum T concentrations. DESIGN: Our study was a community-based evaluation of men's health and aging, including three data collection waves: baseline (T1, 1987-1989) and follow-ups (T2, 1995-1997; T3, 2002-2004). Libido was measured on a 14-point scale assessing self-reported frequency of desire and thoughts/fantasies; low libido was defined as a score of less than 7 of 14. SETTING: We conducted an epidemiological study in greater Boston, Massachusetts. PARTICIPANTS: There were 1632 men aged 40-70 yr at baseline, with follow-up on 922 (56%) at 9 yr (T2) and 623 (38%) at 15 yr (T3). MAIN OUTCOME MEASURES: We assessed total and calculated bioavailable T . RESULTS: Three hundred eighteen (19%) subjects reported low libido at baseline. Libido and T displayed a significant association. However, the difference in mean T levels between those subjects with low libido and those without was small; analyses indicated a 3.4 ng/dl (0.12 nmol/liter) increase in total T per unit increase in libido. Subjects reporting low libido exhibited an increased but modest probability of exhibiting low T. Dividing T concentrations by the number of androgen receptor gene cytosine, adenine, guanine repeats did not enhance associations. CONCLUSIONS: Libido and T concentrations are strongly related at the population level. However, the value of individual patient reports of reduced libido as indicators of low T levels is open to question.     

Prolactin-related testosterone secretion in normal adult men.

The sleep-related increase of plasma testosterone (T) in adult men appears to be related not only to plasma luteinizing hormone (LH) levels but to prolactin (PRL) levels as well, suggesting that PRL may have a stimulatory influence on Leydig cell function. To further investigate the influence of PRL on T secretion, five young adult men were studied on three separate days one week apart. Blood samples were taken every 20 min between 0900 and 1800. At 1000 on each of the three days they received an intramuscular injection of saline, haloperidol 0.25 mg or haloperidol 0.50 mg, in a double-blind design. The blood samples were analyzed for LH, follicle stimulating hormone (FSH), PRL and T. It was hypothesized that there would be a dose-related increase in both PRL and T following drug administration. Mean PRL levels rose promptly and significantly in a dose-related manner in response to the haloperidol, which has strong dopamine blocking effects. By 1600, PRL had returned to control values. In contrast to the PRL response, neither LH nor FSH levels were affected by haloperidol. On the saline control day mean T levels showed the normal decline during daytime hours. After 0.25 mg haloperidol, mean T levels were maintained for several hours, and after 0.50 mg haloperidol, T levels were increased for several hours. These alterations in the normal diurnal pattern of T were statistically significant. They began about 60 min after the corresponding drug-induced increases in PRL levels. This delay between increased PRL and increased T is consistent with the similar delay between the increases of these two hormones that occur at night during sleep. The results of this study lend further support to the hypothesis that PRL is another pituitary hormone that stimulates T secretion in adult men.     

Serum testosterone and bioavailable testosterone correlate with age and body size in hypogonadal men treated with testosterone undecanoate (1000 mg IM--Nebido)

Objective To investigate the loading regimen for intramuscular (IM) testosterone undecanoate (Nebido®) to determine whether testosterone and bioavailable testosterone levels achieved correlate with age or body size of subjects studied. Design Retrospective observational study of testosterone naïve patients and patients previously treated with an alternative testosterone therapy. Patients 51 hypogonadal men (35, 68·6% secondary hypogonadism). 8 (16%) had not previously received testosterone therapy. Measurements Patients received an IM injection of Nebido (1000 mg) at baseline and a second injection after 6 weeks. Serum was assayed at baseline and 18 weeks after commencing Nebido for total testosterone (TT) and SHBG. Bioavailable testosterone was calculated (cBioT) using TT and SHBG. Measurements were taken for weight, body mass index (BMI) and body surface area (BSA). Results Baseline TT (mean 11·5 nmol/l, range 0·3–54·8) increased by 50% after commencing Nebido (17·2 nmol/l (5·4–32·8), P = 0·0001). 75% of subjects had a TT within the reference range (8·0–25·0 nmol/l). Subjects with primary hypogonadism had a higher 18‐week TT [20·9 nmol/l (9·8–32·8) vs. 15·5 (5·4–32·6), P = 0·02] and SHBG [39·2 nmol/l (11–82) vs. 25·7 (9·0–60·0), P = 0·003] although the cBioT was not significantly different [4·9 nmol/l (2·9–7·3) vs. 4·2 (2·0–7·9), P = 0·12]. The 18‐week TT positively correlated with age (R = 0·36, P = 0·01) and negatively correlated with weight (R = –0·38, P = 0·006), BMI (R = –0·42, P = 0·002) and BSA (R =–0·38, P = 0·007). Similarly cBioT correlated with age (R = 0·28, P = 0·04), weight (R = –0·29, P = 0·03), BMI (R = –0·30, P = 0·03) and BSA (R = –0·27, P = 0·05). Age (t = 2·04, P = 0·05) and baseline testosterone (t = –9·26, P < 0·0001) were independent variables of the increase in TT at 18 weeks. Conclusion This starting regimen is simple and provides the majority of men with a TT within the reference range. Age and baseline TT are independent variables of the increase in TT with IM testosterone undecanoate. At week 18 age and body size correlated with the cBioT and TT and this may then be used to estimate dosing frequency for this therapy.     

Pharmacokinetic properties of testosterone propionate in normal men

The pharmacokinetic characteristics of testosterone propionate were studied in normal men after a single im dose of 25 mg testosterone propionate-19,19,19-d3. Plasma levels of testosterone propionate-19,19,19-d3, its active metabolite testosterone-19,19,19-d3, and endogenous testosterone were measured by gas chromatography-mass spectrometry. Testosterone propionate-19,19,19-d3 was gradually transferred from the im injection site to the systemic circulation. The plasma levels of testosterone propionate-19,19,19-d3 were maintained at 2-4 ng/ml between 3 and 36 h after administration. Plasma testosterone-19,19,19-d3 levels were maintained above the physiological testosterone level for 48 h, while plasma levels of endogenous testosterone changed little.     

Why aged men become impotent

Despite frequent erectile impotence in aged men, etiologic data are scarce. We evaluated 121 impotent male veterans (mean age, 68 +/- 5.3 years) to obtain information on potential pathophysiologic mechanisms. Subjects related a complete medical history and underwent physical examination, metabolic assessment, nocturnal penile tumescence monitoring, and vascular and neurologic assessment. The most frequent cause of impotence was the coexistence of neurologic and vascular disorders (30.3%). Other subjects had single causes, including vascular disease (21.1%), diabetic neuropathy (17.1%), nondiabetic neuropathy (10.5%), and psychopathology (9.2%). Remaining patients suffered from adverse drug effects (3.9%), hypogonadism (2.6%), and Peyronie's disease (1.3%). Five patients were objectively impotent on the basis of nocturnal penile tumescence, but otherwise normal. We conclude that geriatric impotence is primarily related to vascular or neurologic dysfunction. However, 15.7% of aged impotent men may have reversible impotence (eg, psychogenic causes or hypogonadism), and an additional 31.5% may have a treatable disorder (eg, penile neuropathy).     

Contribution of bioavailable testosterone assay for the diagnosis of androgen deficiency in elderly men

With age, some men develop symptoms resembling hypogonadism. Several cross-sectional and longitudinal studies have shown a decrease in testosterone levels with ageing in men. This finding has equally been observed in elderly men in good health. Testosterone levels decline progressively as of the thirties, at a rate which remains constant throughout life. While total testosterone levels decrease, sex hormone binding globulin (SHBG) levels on the contrary increase with age, with the result that the levels of free and non-SHBG-bound testosterone (corresponding to the fraction which is bioavailable to target cells) decrease more abruptly than that of total testosterone. Higher LH levels, decreased testosterone response to hCG and less Leydig cells all indicate that ageing induces partial testicular failure. However, the gonadotropic function is also affected in ageing. The hypothalamus-pituitary becomes more sensitive to gonad steroid feedback, LH pulse amplitude decreases, and the LH response to GnRH is blunted compared to the situation in young men. Thus LH level is not a valid index of androgen deficiency in elderly males. None of the androgen-dependent functions (libido, erection, sense of well-being, muscle mass and strength, fat mass, bone mass, erythropoiesis, etc.) are under exclusively androgen control, and there is no elderly male symptom which is completely specific to androgen deficiency. Thus, in elderly men, when clinical symptoms might indicate androgen deficiency, biological confirmation is needed. An assay which is independent of SHBG fluctuations is mandatory. Bioavailable testosterone assay by ammonium sulfate precipitation seems to us to be the optimum method for diagnosing androgen deficiency: it gives a reliable measurement for the testosterone fraction available to target cells, is adapted to clinical practice, and provides results that can be directly compared with current reference values for healthy young men.     

Saliva and serum testosterone following oral testosterone undecanoate administration in normal and hypogonadal men

Since saliva testosterone reflects the testosterone fraction available to target tissues the therapeutic effectiveness of orally administered testosterone undecanoate was assessed by measuring testosterone in serum and saliva. Matched saliva and serum samples were obtained from 12 normal men and 8 hypogonadal men before and at hourly intervals after the oral administration of 120 mg testosterone undecanoate. The test was repeated in 3 men after they had taken 40 mg testosterone undecanoate twice daily for 4 to 5 weeks. Following testosterone undecanoate administration serum and saliva testosterone always showed parallel increases. However, the absorption curves showed a high interindividual variability in the time when maximum concentrations were reached, as well as in the maximum levels themselves. The increases in serum and saliva testosterone were similar in normal and hypogonadal men. In normal men basal levels were reached 4 h after the maximum had occurred, while in hypogonadal men testosterone levels were not different from basal levels 2 h after the maximum. The study shows that testosterone undecanoate is well absorbed from the gut and releases significantly elevated amounts of testosterone which is available to target tissues. As the absorption pattern was always parallel in both fluids, hydrolysis of the circulating testosterone ester by the tissue itself seems to effect no additional increase of testosterone in the tissue.     

Changes in the bioactivity to immunoreactivity ratio of circulating luteinizing hormone in impotent men treated with testosterone undecanoate

Testosterone undecanoate was administered orally (80 mg twice daily) for 30 days to 10 impotent men with mild Leydig cell failure, age 28 to 42 years. Placebo was administered for 30 days both before and at the end of testosterone undecanoate therapy. Serum levels of bioactive LH, immunoreactive LH and testosterone were determined in basal conditions (day zero), 30 days after the first placebo administration, at the 15th and 30th day of testosterone undecanoate therapy, and at the end of the second treatment with placebo (90th day). Bioactive LH was measured by a sensitive and specific in vitro bioassay based on testosterone production by mechanically dispersed mouse Leydig cell preparations. Immunoreactive LH and testosterone were determined by a double-antibody RIA technique. The results were compared with those obtained in 30 untreated normal young men. In the basal state, serum concentrations of immunoreactive LH were significantly higher in the patients (P less than 0.02) than in control subjects, whereas testosterone levels were significantly lower (P less than 0.001) in the impotent men. In contrast, bioactive LH levels and the bioactive LH to immunoreactive LH ratios were similar in the two groups. In the patients, at the 15th day of treatment with testosterone undecanoate, serum levels of testosterone and bioactive LH were significantly higher (P less than 0.01) than basal values, whereas immunoreactive LH concentrations showed no significant changes. Consequently, the bioactive LH to immunoreactive LH ratios rose significantly (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased serum inhibin levels in normal elderly men: evidence for a decline in Sertoli cell function with aging

Compared to young men, normal elderly men have decreased sperm production despite elevated serum gonadotropin levels. To determine whether the seminiferous tubule defect in elderly men includes decreased Sertoli cell function, we measured serum immunoreactive inhibin concentrations in young and elderly men before and after clomiphene citrate (CC) administration. Thirty-eight healthy men, 19 young (aged 22-35 yr) and 19 elderly (aged 65-85 yr), were studied before CC administration. The mean baseline serum inhibin level was significantly lower (P less than 0.001) in the elderly men than in the young men [416 +/- 22 (+/- SE) vs. 588 +/- 30 U/L], while serum immunoreactive FSH and LH levels were higher in the older men, and bioactive FSH levels were similar in the two age groups. Eleven young men and 13 elderly men were studied after 1 week of CC administration. The mean serum inhibin level increased by 71%, from 566 +/- 36 to 970 +/- 82 U/L, in the young men, but it increased by only 24%, from 421 +/- 26 to 520 +/- 38 U/L, in the elderly men. Serum immunoreactive LH and bioactive and immunoreactive FSH concentrations increased to similar levels in both groups after CC administration. We conclude that the seminiferous tubule defect of elderly men includes decreased Sertoli cell function.     

Diurnal rhythms of serum total,free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men

BACKGROUND: Conflicting views are reported on the association between advancing age and gradually diminishing concentrations of serum total testosterone in men. The putative loss of diurnal rhythm in serum total testosterone in older men is reported to be in part due to low concentrations in the morning when compared to concentrations found in young men. We have measured total, free and bioavailable testosterone along with SHBG in samples taken every 30 min throughout a 24-h period in 10 young and eight middle-aged men. RESULTS: Both young and middle-aged men displayed a significant diurnal rhythm in all variables, with a minimum fall of 43% in total testosterone from peak to nadir in all subjects. Subjecting the data to a time series analysis by least squares estimation revealed no significant difference in mesor (P = 0.306), amplitude (P = 0.061) or acrophase (P = 0.972) for total testosterone between the two groups. Comparing bioavailable testosterone in the two groups revealed no significant difference in mesor (P = 0.175) or acrophase (P = 0.978) but a significant difference (P = 0.031) in amplitude. Both groups display a significant circadian rhythm (middle-aged group P < 0.001; young group P = 0.014). Free testosterone revealed a highly significant rhythm in both the young group (P < 0.001) and the middle-aged group (P = 0.002), with no significant difference between the groups in mesor (P = 0.094) or acrophase (P = 0.698). Although analysis of the SHBG data revealed a significant rhythm in the young group (P = 0.003) and the older group (P < 0.001), the acrophase occurred in the mid afternoon in both groups (15.12 h in the young and 15.40 h in the middle-aged). The older men had a significantly greater amplitude (P = 0.044) but again no significant difference was seen in mesor (P = 0.083) or acrophase (P = 0.477) between the two groups. Acrophases for total, bioavailable and free testosterone occurred between 07.00 h and 07.30 h; for SHBG the acrophase occurred at 15.12 h in the young group and 15.40 h in the middle-aged group. CONCLUSIONS: The study suggests that the diurnal rhythm in these indices of androgen status is maintained in fit, healthy men into the 7th decade of life.     

Pharmacokinetics of a new transdermal testosterone gel in gonadotrophin-suppressed normal men

OBJECTIVE: In a phase I single-centre, open, randomized study, the pharmacokinetics of two doses of a transdermal testosterone gel containing 2.5% testosterone were evaluated in 26 healthy male volunteers. DESIGN: To eliminate the influence of endogenous serum testosterone, gonadotrophins and endogenous testosterone secretion were suppressed by a single intramuscular injection of 400 mg norethisterone enanthate. Fourteen men applied 5.0 g and 12 men applied 2.5 g testosterone gel daily for 10 days. Half the men in each group washed the gel off 10 min after it had been applied. RESULTS: In all the men, a marked suppression of LH, FSH, testosterone, dihydrotestosterone (DHT) and oestradiol was observed after norethisterone treatment. Physiological serum concentrations of testosterone were restored during the 10-day treatment period in the group of men applying 5.0 g testosterone gel. Increasing serum concentrations of testosterone from day 1 to day 10 were observed. Oestradiol and DHT concentrations did not exceed normal values. Washing 10 min after gel application did not influence the resorption of testosterone. A dose of 2.5 g testosterone gel was insufficient to achieve physiological serum concentrations of testosterone. CONCLUSION: Testosterone replacement treatment with 5.0 g of this 2.5% testosterone gel is able to achieve constant physiological testosterone concentrations in gonadotrophin-suppressed men. Washing the skin after 10 min does not influence the pharmacokinetic profile and thus significantly reduces the risk of contamination of female partners or infants.     

男性血清生物有效性睾酮与心血管病危险因素个体聚集性的相关性现况调查

目的 通过分析男性血清生物有效性睾酮(Bio—T)与心血管病危险因素个体聚集性的相关性，探讨Bio—T在冠心病发病中的地位。方法 通过现况调查，以1546例男性为研究对象，用放射免疫法测定血清：Bio—T，并检测体重指数、血脂谱、血压、血糖等。结果按Bio-T四分位进行分层(3．54，5．06，8．03nmol／L)分析结果显示男性BMI，SBP，DBP，TC，LDL-C和SG均随Bio—T浓度的下降明显升高，而HDL-C随Bio—T浓度的下降则明显降低。以心血管病危险因素聚集为因变量，Bio—T四等分组设亚变量，调整年龄、吸烟、饮酒、进行logistic：回归分析，结果显示随着Bio—T水平的下降，两个以上心血管病危险因素聚集的危险性升高。结论男性：Bio-T可能是心血管病危险因素聚集的原因之一，雄激素水平的变化与冠心病发病密切相关。