Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men

Hypogonadism is associated with osteoporosis in men. GnRH- agonist-induced hypogonadism increases bone turnover and bone loss in men, but the mechanism underlying these changes is unknown. To determine whether gonadal steroid deprivation increases the skeletal sensitivity to PTH or blunts the ability of PTH to promote 1,25-dihydroxyvitamin D formation, we infused human PTH-(1-34) at a dose of 0.55 U/kg.h for 24 h, in 11 men (ages, 50-82 yr) with locally advanced, node-positive, or biochemically recurrent prostate cancer but no evidence of bone metastases. PTH infusions were performed before initiation of GnRH agonist therapy (leuprolide acetate, 22.5 mg im, every 3 months) and again after 6 months of confirmed GnRH agonist-induced hypogonadism. Serum osteocalcin (OC), bone- specific alkaline phosphatase (BSAP), N-telopeptide (NTX), whole-blood ionized calcium, and 1,25-dihydroxyvitamin D were measured at baseline and every 6 h during each PTH infusion. Urinary NTX and free deoxypyridinoline (DPD) were assessed on spot morning samples before PTH infusion and on 24-h samples collected during the PTH infusions. Sex steroid levels were lowered to the castrate range in all subjects. Baseline serum NTX levels (drawn before PTH infusion) increased from 9.1 +/- 3.7 before leuprolide therapy to 13.9 +/- 5.0 nmol bone collagen equivalents (BCE)/L after leuprolide therapy (P = 0.003). Spot urine NTX collected before PTH infusion increased from 28 +/- 8 before leuprolide therapy to 49 +/- 17 nmol BCE/mmol creatinine after leuprolide therapy (P < 0.001), and urinary DPD increased from 4.7 +/- 1.1 to 7.4 +/- 1.8 nmol BCE/mmol creatinine (P < 0.001). Baseline serum OC and BSAP levels drawn before each PTH infusion did not change before vs. after leuprolide therapy. Serum NTX levels increased significantly during PTH infusion pre-GnRH agonist therapy (P < 0.001), and the rate of increase was greater after 6 months of GnRH agonist-induced hypogonadism (P < 0.01 for the difference in rates of change before and after GnRH agonist administration). Serum OC and BSAP levels decreased during PTH infusion (P < 0.001 for OC and P = 0.002 for BSAP), but the rates of decrease did not differ before or after leuprolide therapy (P = 0.45 for OC and P: = 0.19 for BSAP). Whole-blood ionized calcium levels increased during PTH infusion (P < 0.001), and the rate of increase was greater after GnRH agonist-induced hypogonadism (P = 0.068). Serum 1,25-dihydroxyvitamin D levels increased in response to PTH infusion before leuprolide therapy (P = 0.022), but there was no difference in the rate of increase before or after leuprolide therapy (P = 0.66). The incremental increase in urinary NTX excretion, but not DPD, during PTH infusion was greater after 6 months of leuprolide therapy (P = 0.029 for NTX, P = 0.578 for DPD). We conclude that suppression of sex steroids in elderly men increases the skeletal responsiveness to the bone resorbing effects of PTH infusion but does not affect the response of bone formation markers or 1,25-dihydroxyvitamin D to PTH. Changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men.     

Effects of testosterone suppression on serum levels of hepatitis B surface antigen and HBV-DNA in men

ABSTRACT— Aims/Background: There is epidemiological evidence that progression of hepatitis B virus (HBV)-induced liver disease is adversely influenced by male gender. Furthermore, in male transgenic mice, HBsAg levels increase after puberty, resulting in 4- to 10-fold higher HBsAg levels than in female transgenic mice. Castration reduces HBsAg levels by 90–95%, while substitution of testosterone to castrated animals rapidly increases HBsAg concentrations. We hypothesized that suppression of endogenous testosterone levels may have similar effects on HBsAg serum levels in men, as observed in male mice. Methods: To test our hypothesis, we studied the influence of reversible testosterone suppression by the LHRH-analog triptorelin on serum concentrations of HBsAg and HBV-DNA. Eight male patients, who were chronically infected with HBV, were studied in a prospective interventional study. Results: Triptorelin decreased serum testosterone levels to castration levels for several weeks. However, this reversible testosterone suppression had no effect on HBsAg or HBV-DNA serum concentrations (p>0.05). Conclusions: Suppression of endogenous testosterone levels had no effect on HBsAg levels in men, which points to a different regulation of HBsAg expression in men compared with transgenic mice.     

不同年龄男性血浆睾酮水平的研究

目的　检测男性血浆中总睾酮、游离睾酮的水平 ,观察其变化与年龄的关系。　方法　136例健康男性按不同年龄分成 6组。采用酶联免疫 (ELISA)检测血浆中的总睾酮、游离睾酮 ,分析其与年龄变化的关系。　结果　 2 0～岁、30～岁、4 0～岁、5 0～岁、6 0～岁、70～岁组总睾酮值分别为 :(6 2 0 8± 2 2 75 )、(4 96 0± 1 719)、(5 910± 3 0 5 4 )、(4 96 4± 1 5 31)、(3 96 7± 2 5 14 )及 (4 14 6±2 4 97)mg/L ,游离睾酮值分别为 :(2 3 30 0± 9 5 30 )、(2 2 0 6 0± 12 6 2 7)、(16 2 90± 6 85 8)、(14 782± 6 85 1)、(14 0 0 5± 8 72 4 )及 (12 2 5 6± 7 4 6 2 )ng/L。血浆总睾酮值水平 30～岁组、4 0～岁组、5 0～岁组与 2 0～岁组相比差异无显著性 ,6 0～岁组、70～ 78岁组差异有显著性 (P <0 0 5 ) ;30～岁组、4 0～岁组血浆游离睾酮值水平差异无显著性 ,而 5 0～岁组、6 0～岁组、70～ 78岁组差异有显著性 (P <0 0 5 )。各相邻组两种激素水平差异无显著性 ,血浆游离睾酮比总睾酮发生改变的时间早。　结论　随年龄增长 ,总睾酮、游离睾酮水平逐渐降低 ,游离睾酮的变化出现的较早。二者联合检查 ,将更能准确判断男性激素水平的变化。     

Effects of dietary restriction on serum leptin concentration in obese women.

OBJECTIVE: To investigate the short- and long-term effects of dietary restriction on serum leptin in obese women and the role of the gastrointestinal system in the short-term regulation of leptin production. DESIGN: Clinical longitudinal study of anthropometric and serum leptin changes induced in obese women by a balanced 300 kcal/d very low calorie diet (VLCD), administered either orally or parenterally for 5 d, and by a balanced 900 kcal/d low calorie diet (LCD) lasting six months. SUBJECTS: 20 obese women (age: 38.1 +/- 12.7 y; body mass index (BMI): 40.2 +/- 8.3 kg/m2). RESULTS: Five days following VLCD, a modest, even if significant (P < 0.0001), fall of both body weight (BW) and BMI was observed, along with a dramatic (> 50%) highly significant (P < 0.0001) reduction of circulating serum leptin. Baseline and five-day anthropometric and biochemical findings were closely similar in the group of orally fed subjects, when compared with those of their parenterally fed counterparts. The baseline positive correlation between serum leptin and BMI (p = 0.533) increased (P < 0.05) at the end of the five day VLCD (p = 0.849). A further fall of BW and BMI was observed at day 30 (P < 0.001) and day 180 (P < 0.01) during the 900 kcal/d LCD, while the serum leptin concentration gradually increased until day 180 when it was only slightly but non significantly lower than at baseline. At the end of the study, the correlation between serum leptin and BMI was similar to the baseline (p = 0.562). CONCLUSIONS: Energy restriction causes a fall of serum leptin apparently not mediated by gastrointestinal signals and it seems not to affect the long-term regulatory pathways of circulating leptin.     

Low serum testosterone concentration in middle-aged men with type 2 diabetes

Low concentrations of endogenous androgens have been linked with insulin resistance and atherosclerosis. Men with diabetes have been reported to have lower serum testosterone concentration than non-diabetic men; however, there has never been a large study. The aim of this study was to investigate if endogenous androgen concentration is certainly lower in a relatively large number of Japanese patients with type 2 diabetes compared with healthy men, and to identify what factors may be associated with low serum testosterone concentrations in men with type 2 diabetes. Serum free testosterone concentrations were measured in 524 healthy men and in 331 consecutive Japanese men with type 2 diabetes between 40 and 69 years old. In addition, we investigated the relationships between serum free testosterone concentration and luteinizing hormone (LH) concentration as well as major cardiovascular risk factors including age, blood pressure, plasma lipid concentration, glycemic control (HbA(1c)), and BMI. Serum free testosterone concentrations were lower in men with type 2 diabetes than in healthy men in the 40-49 years group (10.9 +/- 3.3 vs. 14.0 +/- 3.6 pg/ml, P<0.0001), in the 50-59 years group (10.4 +/- 3.2 vs. 12.1 +/- 2.9 pg/ml, P<0.0001), and in the 60-69 years group (9.5 +/- 2.6 vs. 10.5 +/- 2.9 pg/ml, P = 0.0104). A negative correlation was found between serum free testosterone and LH concentrations (r = -0.326, P<0.0001). In conclusion, serum free testosterone concentration is certainly lower in a relatively large number of Japanese patients with type 2 diabetes compared with healthy men with each decade of life between 40 and 69 years old.     

Regulation of serum leptin levels by gonadal function in rats

The aim of this study was to investigate the regulation of serum leptin levels by gender and gonadal steroid milieu. Thus, we measured serum leptin levels by radioimmunoassay in (a) intact male and female rats, (b) female rats at different stages of the estrous cycle and (c) ovariectomized or orchidectomized rats. Gonadectomized groups were or were not implanted with silastic capsules (10 or 30 mm in length, 1.519mm internal diameter; 3.06 mm external diameter) containing estradiol or testosterone and decapitated two weeks later. We found (i) intact female rats weighing 50 g, 250 g and 300 g exhibited higher serum leptin concentrations than intact male rats of similar body weight; (ii) leptin concentrations were not affected by the phase of the estrous cycle; (iii) two weeks after gonadectomy serum leptin concentrations increased in both male (from 4.47+/-1.87 to 8.76+/-1.24 ng/ml) and female (from 1.97+/-0.46 to 5.29+/-0.51 ng/ml) rats. The ovariectomy-induced increase in serum leptin levels was not dependent, at least completely, on changes in body weight since it could be observed when comparisons were made between ovariectomized rats and intact rats in estrus matched for body weight. In contrast the effect of orchidectomy on serum leptin levels appears to be dependent on changes in body weight since it was no longer observed when comparisons were made with a group of intact male rats matched for body weight. In conclusion, these results suggest that serum leptin concentrations are controlled by gonadal function either directly or as a consequence of changes in body weight.     

Serum leptin concentration, body composition, and gonadal hormones during puberty.

BACKGROUND: Recent evidence has suggested that leptin concentration is associated with gonadal hormone levels, and that changes in leptin concentration may trigger the onset of reproductive function in children. However, the concurrent changes in body composition during puberty make the independent associations between leptin and gonadal hormone concentrations in children difficult to resolve. METHODS: To investigate the nature of associations between leptin levels and pubertal maturation, serum concentrations of leptin, estradiol, and testosterone and body composition measures were examined in a sample of 152 healthy pre-pubertal, pubertal, and post-pubertal children. RESULTS: Leptin concentration was nearly three-fold higher in post-pubertal girls than in pre-pubertal girls, but was relatively similar in pre- and post-pubertal boys. Significant sex differences in leptin concentration existed in prepubertal, pubertal and post-pubertal children, and these remained significant after controlling for adiposity. After adjusting for total body fat, fat-free mass and age, testosterone concentration was negatively associated with leptin levels in pubertal boys, while estradiol concentration was positively associated with leptin level in pubertal girls. CONCLUSIONS: Girls have higher serum leptin concentration before, during, and after puberty than boys, even after accounting for the development of greater female adiposity. Although other factors may be involved, sexual dimorphism in leptin concentrations during puberty appears to be partly due to a stimulatory effect of estradiol on leptin concentration in females and a suppressive effect of testosterone on leptin concentration in males.     

Plasma androgen levels in men after oral administration of testosterone or testosterone undecanoate.

Plasma testosterone and androstenedione levels in men were measured after oral administration of free testosterone and testosterone undecanoate. Both androgens were determined by simultaneous, specific radioimmunoassays after separation and isolation by thin layer chromatography. While free unesterified testosterone had no effect on plasma androgen levels, a striking increase of both testosterone and androstenedione levels was noted after administration of testosterone undecanoate, which is otherwise only achieved by parenteral testosterone application. This effect of testosterone undecanoate is probably due to absorption via the lymph rather than via the portal vessels so that peripheral circulation is reached before metabolism in the liver. Testosterone undecanoate promises to be an effective medication for oral androgen replacement.     

Acute suppression of circulating testosterone levels by cortisol in men

The effect of acute activation of the ACTH-adrenal axis on circulating testosterone (T) levels was investigated. Elevation of circulating cortisol resulting from insulin-induced hypoglycemia or the administration of hydrocortisone was followed by a rapid decrease in serum T levels, without accompanying changes in LH or PRL. These findings suggest that hypercortisolism of endogenous or exogenous sources suppresses T secretion by a direct action on the testis. This adrenal-testicular axis may have biological implications on the reproductive adaptation to stress.     

Effects of testosterone suppression in young men by the gonadotropin releasing hormone antagonist cetrorelix on plasma lipids, lipolytic enzymes, lipid transfer proteins, insulin, and leptin.

We investigated in a pilot study the effect of testosterone suppression on lipoprotein metabolism, insulin, and leptin in 10 men who were treated either with cetrorelix, an antagonist of gonadotropin releasing hormone, or with placebo (P). Group C + C (n = 4) was treated with 10 mg cetrorelix as daily subcutaneous injections for five days and with a subsequent injection of 60 mg cetrorelix depot. Group C + P (n = 3) received 10 mg cetrorelix as daily intramuscular injections for five days and a subsequent injection of placebo depot. Group P + P (n = 3) received placebo both as daily and depot injections. Treatment with cetrorelix reversibly suppressed testosterone to castrate levels for three weeks in group C + C and for one week in group C + P. Compared to baseline, treatment with cetrorelix increased serum levels of apolipoprotein (apo) A-I, HDL subclass LpA-I, insulin, and leptin. In the group P + P, treatment with placebo was not associated with any change of these parameters. Compared to baseline and group P + P, treatment with cetrorelix in groups C + C and C + P did not lead to considerable or consistent changes in the plasma activities of lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), lipoprotein lipase, and hepatic lipase (HL). Only the pooled data of groups C + C and C + P unraveled small but statistically significant decreases of HL and CETP activities in response to cetrorelix. In conclusion, the small or absent effects of cetrorelix on LCAT, CETP, PLTP, LPL, and HL indicate that testosterone regulates HDL levels by other metabolic pathways. The increases of insulin and leptin in response to cetrorelix suggest that testosterone influences HDL metabolism also via obesity and insulin resistance. These effects, however, are rather in contrast to the HDL raising effect of suppressed testosterone.     

Relationship of serum leptin levels with body composition and sex steroid and insulin levels in men and women

Whether the higher serum leptin levels in women are due to gender differences in fat mass or to other factors such as sex steroids remains unclear. In addition to sex steroids, serum insulin levels also appear to be related to leptin levels, although whether this effect is independent of the effects of body composition is unclear. The purpose of this study was to identify the major determinants of circulating serum leptin levels. We studied a large, population-based cohort of 345 men (23 to 90 years), 137 premenopausal women (21 to 54 years), and 212 postmenopausal women (34 to 94 years), including 47 women on hormone replacement therapy (HRT). Serum leptin levels were related to body composition as assessed by dual-energy x-ray absorptiometry (DEXA) and to circulating sex steroid and insulin levels. Serum leptin levels remained significantly higher in women versus men even after adjustment for fat mass, and leptin levels were significantly correlated with fat mass independently of age. By univariate analyses, logarithmically transformed serum leptin levels correlated positively with bioavailable estrogen ([E] estradiol plus estrone) in postmenopausal women not on HRT, and negatively with total and bioavailable testosterone (T) levels in men. Serum insulin levels were directly related to leptin levels regardless of gender and age. By multivariate analyses, fat mass, lean mass, and insulin levels were the strongest predictors of leptin levels in all groups. In addition, bioavailable E entered the model in the postmenopausal women not on HRT. These studies indicate that the fat mass, lean mass, and insulin level are the major determinants of the serum leptin level in adults. Moreover, after adjusting for these variables, bioavailable E also explains a significant proportion of the variance in leptin levels among postmenopausal women not on HRT.     

Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men

Circulating testosterone (T) levels have behavioral and neurological effects in both human and nonhuman species. Both T concentrations and neuropsychological function decrease substantially with age in men. The purpose of this prospective, longitudinal study was to investigate the relationships between age-associated decreases in endogenous serum T and free T concentrations and declines in neuropsychological performance. Participants were volunteers from the Baltimore Longitudinal Study of Aging, aged 50-91 yr at baseline T assessment. Four hundred seven men were followed for an average of 10 yr, with assessments of multiple cognitive domains and contemporaneous determination of serum total T, SHBG, and a free T index (FTI). We administered neuropsychological tests of verbal and visual memory, mental status, visuomotor scanning and attention, verbal knowledge/language, visuospatial ability, and depressive symptomatology. Higher FTI was associated with better scores on visual and verbal memory, visuospatial functioning, and visuomotor scanning and a reduced rate of longitudinal decline in visual memory. Men classified as hypogonadal had significantly lower scores on measures of memory and visuospatial performance and a faster rate of decline in visual memory. No relations between total T or the FTI and measures of verbal knowledge, mental status, or depressive symptoms were observed. These results suggest a possible beneficial relationship between circulating free T concentrations and specific domains of cognitive performance in older men.     

Effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or gonadotropin-releasing hormone antagonist on spermatogenesis and intratesticular steroid levels in normal men

CONTEXT: Combination of a GnRH antagonist (acyline), types I and II, 5alpha-reductase inhibitor (dutasteride) or levonorgestrel (LNG) with testosterone (T) treatment may augment the suppression of spermatogenesis and intratesticular (iT) steroids. OBJECTIVE: The objective of this study was to assess the effects of combined hormonal contraceptive regimens on germ cell populations and iT steroids. DESIGN, SETTING, AND PARTICIPANTS: Twenty-nine normal health men enrolled in this prospective, randomized, 14-wk study at the University of Washington. INTERVENTION(S): Twenty-two men (n = 5-6/group) received 8 wk of T enanthate (TE; 100 mg, i.m., weekly) combined with 1) 125 microg LNG daily, orally; 2) 125 microg LNG plus 0.5 mg dutasteride daily, orally; 3) 300 microg/kg acyline twice weekly, s.c.; or 4) 125 microg LNG daily, orally, plus 300 microg/kg acyline twice weekly, s.c. Subjects then underwent a vasectomy and testicular biopsy. Control men (n = 7) proceeded directly to surgery. MAIN OUTCOME MEASURE(S): The main outcome measures were germ cells and iT steroids [T, dihydrotestosterone, 3alpha- and beta-androstanediol (Adiol), and estradiol (E2)]. RESULTS: High iT levels of all androgens (6- to 123-fold serum levels) and E2 (407-fold serum levels) were found in control men. iTT (1.9-2.6% control; P < 0.001) and iT3betaAdiol (16-34% control; P < 0.05) levels decreased with all treatments. iT dihydrotestosterone (13-29% control; P < 0.05) and iT3alphaAdiol (44-47% control; P < 0.05) levels decreased with all but the TE plus LNG treatment. iTE2 levels decreased only in the TE plus acyline group (28% control; P = 0.01). Germ cells from type B spermatogonia onward were suppressed, with no differences between groups found. Variable sites of impairment of germ cell progression were evident between men (spermagonial maturation, meiosis 1 entry, and spermiation). Other than a negative correlation between iT3alphaAdiol and haploid germ cell number (P < 0.006), no correlations between germ cell number and gonadotropins, sperm concentration, or iT steroids were found. CONCLUSIONS: A similar high testicular:serum gradient exists for E2 and T in normal men, and 8 wk of gonadotropin suppression markedly reduces iTT, with 5alpha-reduced androgens and E2 levels decreasing to a much lesser degree. The heterogeneity of the germ cell response, regardless of treatment, gonadotropins or iT steroids, points to the individual sensitivity of sites in germ cell development, which is worthy of additional exploration.     

Association between serum leptin concentration and white blood cell count in middle-aged Japanese men and women

BACKGROUND: Leptin's hematopoietic or proinflammatory role has been experimentally reported. We investigated whether serum leptin concentrations are associated with white blood cell (WBC) counts in humans. METHODS: Serum leptin concentrations of Japanese civil servants aged 40 to 59 years (1082 men and 200 women) were analyzed in relation to their WBC count. Serum leptin concentrations and WBC counts were measured by radioimmunoassay and automated particle counter respectively, using samples obtained at the time of the participants' annual health checkups. RESULTS: The geometric mean (+/-geometric standard deviation) leptin concentrations were 3.25 +/- 1.82 ng/mL and 6.25 +/- 3.99 ng/mL, and the geometric mean WBC counts, 5770 +/- 1269/mm(3) and 5107 +/- 1228/mm(3), in men and women respectively. The WBC count adjusted for age, body mass index (BMI), physical activity, and drinking and smoking habits increased together with the increase in leptin concentration. Multiple linear regression against WBC count by the leptin concentration and those covariates revealed a significant and independent association with serum leptin concentration especially in women (standardized beta = 0.31, p < 0.001), and also in men (standardized beta = 0.17, p < 0.001). BMI was not significantly associated with WBC counts in the multivariate model adjusting for leptin levels in both sexes. CONCLUSIONS: Our results are in line with leptin's hematopoietic or proinflammatory functions. The increased WBC counts often observed in obese people would be mediated by the increased leptin concentration.     

Low serum testosterone and mortality in older men

CONTEXT: Declining testosterone levels in elderly men are thought to underlie many of the symptoms and diseases of aging; however, studies demonstrating associations of low testosterone with clinical outcomes are few. OBJECTIVE: The objective of the study was to examine the association of endogenous testosterone levels with mortality in older community-dwelling men. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, population-based study of 794 men, aged 50-91 (median 73.6) yr who had serum testosterone measurements at baseline (1984-1987) and were followed for mortality through July 2004. MAIN OUTCOME MEASURE: All-cause mortality by serum testosterone level was measured. RESULTS: During an average 11.8-yr follow-up, 538 deaths occurred. Men whose total testosterone levels were in the lowest quartile (<241 ng/dl) were 40% [hazards ratio (HR) 1.40; 95% confidence interval (CI) 1.14-1.71] more likely to die than those with higher levels, independent of age, adiposity, and lifestyle. Additional adjustment for health status markers, lipids, lipoproteins, blood pressure, glycemia, adipocytokines, and estradiol levels had minimal effect on results. The low testosterone-mortality association was also independent of the metabolic syndrome, diabetes, and prevalent cardiovascular disease but was attenuated by adjustment for IL-6 and C-reactive protein. In cause-specific analyses, low testosterone predicted increased risk of cardiovascular (HR 1.38; 95% CI 1.02-1.85) and respiratory disease (HR 2.29; 95% CI 1.25-4.20) mortality but was not significantly related to cancer death (HR 1.34; 95% CI 0.89-2.00). Results were similar for bioavailable testosterone. CONCLUSIONS: Testosterone insufficiency in older men is associated with increased risk of death over the following 20 yr, independent of multiple risk factors and several preexisting health conditions.