Kinetics of testosterone recovery in clinically localized prostate cancer patients treated with radical prostatectomy and subsequent short-term adjuvant androgen deprivation therapy

Androgen deprivation therapy (ADT) is a standard treatment for metastatic, recurrent and locally advanced prostate cancer (PCa). The aim of this study is to investigate the timing and extent of testosterone recovery in clinically localized PCa patients treated with radical prostatectomy (RP) and subsequent short-term adjuvant ADT. A total of 95 localized PCa patients underwent RP and 9-month adjuvant ADT were included in this prospective study. Serum testosterone level was measured before adjuvant ADT, at ADT cessation, and at 1, 3, 6, 9 and 12 months after cessation of ADT. A Cox proportional hazards model was used to assess variables associated with the time of testosterone normalization. The results showed that median patient age was 67 years and median testosterone level before adjuvant ADT was 361 (230–905) ng dl⁻¹. All patients finished 9-month adjuvant ADT and achieved castrate testosterone level. At 3 months after ADT cessation, testosterone recovered to supracastrate level in 97.9% patients and to normal level in 36.9% patients. The percentage of patients who recovered to normal testosterone level increased to 66.3%, 86.3% and 92.6% at 6, 9 and 12 months, respectively. Cox regression model found that higher baseline testosterone level (≥300 ng dl⁻¹) was the only variable associated with a shorter time to testosterone normalization (hazard ratio: 1.98; P = 0.012). In conclusion, in most patients, testosterone recovered to supracastrate level at 3 months and to normal level at 12 months after 9-month adjuvant ADT cessation. Patients with higher baseline testosterone level need shorter time of testosterone normalization.     

Duration of androgen deprivation therapy and nadir of testosterone at 20 ng/dL predict testosterone recovery to supracastrate level in prostate cancer patients who received external beam radiotherapy

Objectives

To determine the predictors of testosterone recovery after termination of androgen deprivation therapy in high/intermediate‐risk prostate cancer patients receiving external beam radiation therapy with neoadjuvant and adjuvant androgen deprivation therapy.

Methods

A total of 82 patients who underwent external beam radiation therapy with androgen deprivation therapy for prostate cancer were retrospectively analyzed. Serum testosterone levels after androgen deprivation therapy terminations were studied. Cox proportional hazard models and the Kaplan–Meier method were used for statistical analysis.

Results

Median age, baseline testosterone, nadir testosterone and duration of androgen deprivation therapy were 73 years, 456 ng/dL, 16 ng/dL and 26 months, respectively. Androgen deprivation therapy duration of 33 months (hazard ratio 0.13; P = 0.0018), nadir testosterone of 20 ng/dL (hazard ratio 0.35; P = 0.0112) and testosterone >50 ng/dL at 6 months after androgen deprivation therapy termination (hazard ratio 0.21; P = 0.0075) were significantly associated with testosterone recovery to normal levels (200 ng/dL) on multivariate analysis. Androgen deprivation therapy duration of 33 months (hazard ratio 0.31; P = 0.0023) and nadir testosterone of 20 ng/dL (hazard ratio 0.38; P = 0.0012) were significantly associated with testosterone recovery to the supracastrate level (50 ng/dL) on multivariate analysis. After dividing patients into three risk groups, the rate of testosterone recovery to the normal level after 2 years of androgen deprivation therapy termination was 100% in the low‐risk group versus 20.8% in the high‐risk group (P < 0.0001); the rate of testosterone recovery to the supracastrate level was 100% in the low‐risk group versus 51.5% in the high‐risk group (P < 0.0001).

Conclusions

Duration of androgen deprivation therapy and achievement of nadir testosterone 20 ng/dL both predict testosterone recovery to the supracastrate level in prostate cancer patients undergoing external beam radiation therapy with androgen deprivation therapy.     

Prolactin and Leydig cells: biphasic effects of prolactin on LH-, T3- and GH-induced testosterone/oestradiol secretion by Leydig cells in pubertal rats

The effect of rat prolactin (rPRL) on basal and LH-, GH- and T3-mediated testosterone and oestradiol secretion was studied in pubertal rat Leydig cells. Purified Leydig cells were cultured for 24 h at 37 degrees C in a medium containing 4% foetal calf serum (FCS). The medium was then replaced with fresh medium containing different concentrations of rPRL (5-400 ng/mL) for 48 h at 34 degrees C without FCS. rPRL increased testosterone secretion by Leydig cells at doses of 50-400 ng and maximum stimulation was observed at a dose of 200 ng. Oestradiol secretion was parallel to that of testosterone except at low doses (5-50 ng/mL). To assess the modulatory effect of rPRL on LH-, GH- and T3-induced Leydig cell testosterone and oestradiol secretion, minimum (50 ng) and maximum (200 ng) effective doses of rPRL were co-administered with LH (25/100 ng), GH (10/50 ng) and T3 (25/50 ng). Co-administration of rPRL (50/100 ng) with T3 (25/50 ng) decreased testosterone secretion. While co-administration of T3 (25 ng) decreased rPRL-induced oestradiol secretion, the latter was unaltered at a dose of 50 ng T3. A minimum effective dose of rPRL (50 ng) plus LH (25 ng) stimulated both testosterone and oestradiol secretion. While a maximum effective dose of rPRL (200 ng) did not alter LH (25 ng)-induced testosterone and oestradiol secretion, it inhibited testosterone secretion induced by 100 ng LH and increased oestradiol secretion. Both doses of rPRL (50, 200 ng) plus GH (10/50 ng) inhibited testosterone secretion when compared with testosterone secretion induced by either GH or PRL alone and stimulated oestradiol secretion. The present in vitro study indicates that rPRL stimulates both testosterone and oestradiol secretion by Leydig cells and that this effect can be modulated by LH, GH and T3.     

【特刊综述】男性睡眠障碍和睾酮的关系

血浆睾酮水平呈现昼夜节律变化，睡眠时达高峰，午后降至最低，伴随一个叠加的具有反映黄体生成素（LH）脉冲式分泌基础节律的每90分钟一次脉冲的超昼夜节律。能促进睾酮增加的是睡眠而不是昼夜节律，依赖并需要至少三个小时正常结构的睡眠。多种睡眠障碍包括睡眠质量、持续时间异常、昼夜节律紊乱、睡眠呼吸障碍可能会导致睾酮水平下降。睡眠限制或昼夜节律紊乱不依赖于性激素结合球蛋白而直接影响睾酮的证据或共存疾病的存在是模棱两可的，总的看起来证据不足。在对年龄和肥胖进行调整后，阻塞性睡眠呼吸暂停（OSA）看起来似乎对睾酮没有直接影响。尽管如此，也许存在一种潜在的由OSA对肥胖的影响所介导的的间接因果过程。大多数研究中采用持续正压通气（CPAP）治疗中到重度OSA并没有真正提高睾酮水平。相反，体重减轻却的确提高了睾酮水平，并且与体重下降情况成线性比例。睾酮治疗除了具有非常短暂的毒副作用，对OSA并没有不利影响。睡眠质量对睾酮影响的研究数据可能取决睾酮给药是作为替代、超治疗剂量还是在滥用的范围。实验数据显示睾酮可以调节睡眠限制的主观症状的个体易患性。睾酮低下可能会影响整个睡眠质量，给予替代剂量可以得到改善。大剂量外源性雄激素和促进合成或促进雄激素产生的甾体激素滥用与睡眠持续时间和结构异常有关。     

Some effects of furazolidone on the testis and plasma levels of testosterone, luteinizing hormone and prolactin in mature male turkeys

Adult male turkeys were treated orally with furazolidone at doses of 1, 2.5, S or 20 mg/kg for 14 days and their plasma analysed for luteinizing hormone (LH), testosterone and prolactin (PRL) concentrations before, during and after treatment. At 20 mg/kg the drug produced a significant decrease in the plasma levels of LH and testosterone at the end of treatment, whereas at 5 mg/kg the drug had no significant effect. Prolactin concentrations were unaffected by any of the drug doses used. Intramuscular injection of luteinizing hormone releasing hormone (LHRH) at a dose of 5 μg/kg produced after 30 min a significant rise in plasma levels of LH, an effect that was decreased significantly by treatment with 20 mglkg furazolidone. Incubation of normal turkey semen with graded doses of furazolidone or nitrofura-zone for up to 30 min resulted in a dose- and time-dependent decrease in sperm motility. At a concentration of 20 mg/ml a complete absence of sperm motility was observed after incubation with either drug, although, on the whole, nitrofurazone seemed more potent than furazolidone as a sperm-immobilizing agent. Histological changes occured in the 20 mg/kg group and consisted of a decrease in spermatocyte production, corrugation of sperm cell nuclear envelopes and distention of the endoplasmic reticulum of elongate spermatids. It is concluded that furazolidone depresses pituitary LH output but may, in addition, directly affect spermatogenesis and sperm motility.     

Effect of sleep deprivation on the physiological status of rat testis

The effect of alteration of central turnover of monoamines on the intratesticular mechanisms in the testis of rats was studied after REM sleep-deprivation. The reduction in the weights of ventral prostate, seminal vesicles and decreased activity of beta-glucuronidase in kidney reflected decreased availability of testosterone to the target organs. Decreased activities of lysosomal enzymes, acid phosphatase and beta-glucuronidase were associated with a decreased steroidogenic activity in the testis. The active mediation of lysosomal enzymes in the testicular function under altered condition was indicated.     

The effect of sleep deprivation and disruption on DNA damage and health of doctors

Observational studies have highlighted the detrimental health effects of shift work. The mechanisms through which acute sleep deprivation may lead to chronic disease have not been elucidated, but it is thought that increased DNA damage or decreased repair can lead to disease. The objective of this study was to examine the effects of acute sleep deprivation on DNA damage. This was a cross-sectional observational study on 49 healthy, full-time doctors. Baseline blood was sampled from each participant after three consecutive days of adequate sleep. Participants (n = 24) who were required to work overnight on-site had additional blood sampled on a morning after acute sleep deprivation. DNA damage and expression of DNA repair genes were quantified. Information on health, working patterns and sleep diaries were collected. Independent t-tests were used to compare differences between groups and standardised mean differences expressed as Cohen's d. Overnight on-site call participants had lower baseline DNA repair gene expression and more DNA breaks than participants who did not work overnight (d = 1.47, p = 0.0001; and 1.48, p = 0.0001, respectively). In overnight on-site call participants, after acute sleep deprivation, DNA repair gene expression was decreased (d = 0.90, p = 0.0001) and DNA breaks were increased (d = 0.87, p = 0.0018). Sleep deprivation in shift workers is associated with adverse health consequences. Increased DNA damage has been linked to the development of chronic disease. This study demonstrates that disrupted sleep is associated with DNA damage. Furthermore, larger prospective studies looking at relationships between DNA damage and chronic disease development are warranted, and methods to relieve, or repair, DNA damage linked to sleep deprivation should be investigated.     

Influence of dutasteride treatment on serum hormone levels and aging male symptoms in patients with benign prostatic enlargement

Objectives

To clarify the effects of dutasteride on serum hormone levels and aging male symptoms in patients with benign prostatic enlargement.

Methods

The present prospective study was carried out in 110 symptomatic benign prostatic enlargement patients treated with daily administration of 0.5 mg dutasteride. We analyzed serum hormonal levels and aging related symptoms using a validated Aging Male Symptom questionnaire at baseline and after 3 months of dutasteride treatment.

Results

The mean total testosterone, free testosterone and luteinizing hormone levels after dutasteride treatment were approximately 20% higher than those at baseline. The percentage increases in total and free testosterone levels were negatively correlated with these baseline levels. Baseline age, levels of total testosterone and free testosterone, and the changes in the rate of luteinizing hormone after dutasteride treatment tended to be correlated with an increase in the rate of total testosterone and free testosterone after dutasteride treatment. In a subgroup of 26 patients with moderate‐to‐severe aging male symptoms, poor morning erection and free testosterone levels <8.5 pg/mL, total aging male symptoms, and somatic symptoms scores significantly decreased after dutasteride treatment with an increase of total and free testosterone.

Conclusions

The increase of endogenous free testosterone and total testosterone by dutasteride might bring additional benefits of improvement of aging male‐related symptoms, especially in patients with lower free testosterone baseline levels and moderate‐to‐poor aging‐related symptoms.     

Impairment of attentional networks after 1 night of sleep deprivation

Here, we assessed the effects of sleep deprivation (SD) on brainactivation and performance to a parametric visual attentiontask. Fourteen healthy subjects underwent functional magneticresonance imaging of ball-tracking tasks with graded levelsof difficulty during rested wakefulness (RW) and after 1 nightof SD. Self-reports of sleepiness were significantly higherand cognitive performance significantly lower for all levelsof difficulty for SD than for RW. For both the RW and the SDsessions, task difficulty was associated with activation inparietal cortex and with deactivation in visual and insularcortices and cingulate gyrus but this pattern of activation/deactivationwas significantly lower for SD than for RW. In addition, thalamicactivation was higher for SD than for RW, and task difficultywas associated with increases in thalamic activation for theRW but not the SD condition. This suggests that thalamic resources,which under RW conditions are used to process increasingly complextasks, are being used to maintain alertness with increasinglevels of fatigue during SD. Thalamic activation was also inverselycorrelated with parietal and prefrontal activation. Thus, thethalamic hyperactivation during SD could underlie the reducedactivation in parietal and blunted deactivation in cingulatecortices, impairing the attentional networks that are essentialfor accurate visuospatial attention performance.     

Time course of serum testosterone and luteinizing hormone levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer

INTRODUCTION: In order to elucidate the influence of hormone-releasing hormone (LH-RH) agonist therapy cessation on pituitary/testicular function and its clinical implications, we investigated prospectively hormonal (luteinizing hormone: LH; testosterone: T) responses in patients with prostate cancer who received long-term LH-RH 10 agonist therapy. PATIENTS AND METHODS: A consecutive 32 patients who had received LH-RH agonist therapy over 24 months were enrolled. As a baseline, T and LH were measured at the time of LH-RH agonist therapy cessation, monthly for 3 months, and subsequently, every 3 months. RESULTS: The median duration of LH-RH agonist therapy was 30 months (24-87 months) with median follow-up duration of 24 months following cessation. All patients had castrated T levels and suppressed LH levels at baseline. Median duration of castrated T levels following cessation was 6 months. Median time to normalization of T levels was 24 months. LH levels returned to normal within 3 months in all cases. Patients who received androgen deprivation therapy for 30 months or longer required a longer time for recovery of T levels. Patients over 65 years of age showed a statistically significant longer time for recovery of T levels (P=0.0167). CONCLUSIONS: Long-term LH-RH agonist therapy has remarkable effects on serum T level that last for a significant time after cessation, a fact that should be applied to the interpretation of both PSA and serum T levels after cessation of androgen deprivation therapy.     

Recovery of serum testosterone after neoadjuvant androgen deprivation therapy and radical radiotherapy in localized prostate cancer

OBJECTIVE: To prospectively evaluate the time-course of recovery of serum testosterone levels after a short course of luteinizing hormone-releasing hormone analogue (LHRHa) and radical radiotherapy to the prostate. PATIENTS AND METHODS: Testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were sequentially measured prospectively in 59 men who received short-course LHRHa treatment and radiotherapy for localized prostate cancer. Measurements were made before treatment (baseline), during LHRHa treatment, and at 6, 12, 18, 24 and >40 weeks after the last LHRHa injection. RESULTS: The median (range) time from the first to last LHRHa injection was 116 (54-194) days. The mean (95% confidence interval) testosterone levels (in nmol/L) at baseline, during treatment and at 6, 12, 18, 24 and >40 weeks afterward were 12.0 (10.8-13.1), 0.6 (0.5-0.7), 1.4 (0.6-2.2), 11.4 (9.7-13), 12.2 (10.5-14), 10.4 (8.9-12) and 11.7 (10.5-13). Four men had low baseline testosterone levels (<6.1 nmol/L). At 6 weeks after the last LHRHa injection, no men had testosterone levels in the 'normal' range; 35% were in the normal range at 12 weeks, 85% at 18 weeks, 89% at 24 weeks, and 96% at 1 year. CONCLUSION: After LHRHa treatment and radiotherapy, the testosterone levels of most men had recovered to normal by 18-24 weeks after the last LHRHa injection.     

Serum testosterone levels after medical or surgical androgen deprivation: A comprehensive review of the literature

Androgens and the androgen receptor play a role in the progression of prostate cancer. Androgen deprivation therapy (ADT) is a mainstay in the treatment of metastatic prostate cancer. ADT is expected to reduce serum testosterone levels from a normal level of about 500 to 600 ng/dl (17.3–20.8 nmol) down to castration levels. Traditionally, castration was considered to be achieved if testosterone levels were lowered to a threshold of 50 ng/dl (1.73 nmol/l), a definition determined more by measurement methods derived from the use of old assay methods than by evidence. Serum testosterone levels in three-quarter patients after surgical castration drop to less than 20 ng/dl (0.69 nmol/l). Ineffective suppression of testosterone is currently poorly recognized and may possibly have an effect of prostate cancer mortality. Persistent levels of serum testosterone after castration are mainly derived from adrenal androgens. Furthermore, the arrival of new therapies targeting androgen synthesis and androgen receptor activity has renewed interest on serum testosterone. This review discusses the biosynthetic pathway for androgen synthesis in humans and provides a comprehensive review of serum testosterone levels after surgical or medical castration. This review assesses serum testosterone levels after surgical castration and different pharmacologic castration in patients with prostate cancer under ADT, and ineffective testosterone suppression. The author proposes methods to better lower serum testosterone levels during ADT.     

Testosterone and erectile function recovery after radiotherapy and long-term androgen deprivation with luteinizing hormone-releasing hormone agonists

OBJECTIVE: To study the recovery of testosterone levels and erectile function in men who received radiotherapy plus long-term adjuvant androgen deprivation (LTAD) with luteinizing hormone-releasing hormone (LHRH) agonists. PATIENTS AND METHODS: From April 2000 to July 2001, men who had completed prostate radiotherapy with > or = 2 years of LTAD, and had their last LHRH agonist injection at least 6 months before, were invited to participate. At study entry, the men completed the International Index of Erectile Function (IIEF), and their serum total testosterone (TT), prostate-specific antigen, LH, follicle-stimulating hormone, haemoglobin, and body mass were measured. This assessment was repeated at 1 year. RESULTS: In all, 20 men were recruited, with a mean (range) age of 70 (55-81) years. Defining a normal TT level as > or = 8.0 nmol/L, the median time to a normal level was 2.3 years (95% confidence interval (CI), 1.9-4.2). The median duration of castrate TT levels was 8 months (95% CI, 6.2-14.9). LH recovered before TT, suggesting that the rate-limiting step in the recovery of TT may be at the testicular level. The median time to recovery of normal LH levels was 3.8 months, compared to 8.0 months to reach supracastrate TT levels, and 2.3 years to reach normal TT levels. Age and the LH/TT ratio were associated with the time to recovery of both supracastrate and normal levels of TT. The IIEF was completed by 17 men; there were no significant changes in the scores in any domain of the IIEF during the study. CONCLUSIONS: Most men recover supracastrate testosterone levels after LTAD and external beam radiotherapy, but recovery of 'normal' testosterone levels is slow. Few men recover potency and sexual desire. The patients age and LH/TT ratio may be predictive of the time to recovery of both supracastrate and normal testosterone levels.     

Suppression of testosterone stimulates recovery of spermatogenesis after cancer treatment

It is important to develop methods to prevent or reverse the infertility caused by chemotherapy or radiation therapy for cancer in men. Radiation and some chemotherapeutic agents kill spermatogonial stem cells, but we have shown that these cells survive in rats, although they are unable to differentiate. There is evidence that this phenomenon also occurs in men. The block to spermatogonial differentiation in rats is caused by some unknown change, either in the spermatogonia or the somatic elements of the testis, such that testosterone inhibits spermatogonial differentiation. In the rat, the spermatogenesis and fertility lost following treatment with radiation or some chemotherapeutic agents can be restored by suppressing testosterone with gonadotropin releasing hormone (GnRH) agonists or antagonists, either before or after the cytotoxic insult. The applicability of this procedure to humans is still unknown. Some anticancer regimens may kill all the stem cells, in which case the only option would be spermatogonial transplantation. However, in some cases stem cells survive and there is one report of stimulation of recovery of spermatogenesis with hormonal treatment. Clinical trials should focus on treating patients with hormones during or soon after anticancer treatment. The hormone regimen should involve suppression of testosterone production with minimum androgen supplementation used to improve the diminished libido.     

异丙酚对异相睡眠剥夺大鼠海马谷氨酸和γ-氨基丁酸释放的影响

目的 探讨异丙酚对24 h异相睡眠剥夺大鼠海马谷氨酸(Glu)和γ-氨基丁酸(γ-GABA)释放的影响.方法 健康雄性SD大鼠16只,成功完成24 h异相睡眠剥夺实验后,随机分为2组(n=8),自然睡眠组(N组)腹腔注射5%脂肪乳剂3 ml,异丙酚组(P组)腹腔注射异丙酚100mg/kg.于异相睡眠剥夺前(基础状态)、异相睡眠剥夺24 h时(T1)、异相睡眠剥夺结束后1 h(T2)、3 h(T3)和6 h(T4)收集2组海马微透析液,检测Glu和γ-GABA的浓度.结果 与基础值比较,N组和P组T1-3时海马微透析液内Glu、γ-GABA浓度升高,N组T4时上述指标仍较高;与T1时比较,N组和P组T3,4时上述指标降低(P＜0.05或0.01).两组间Glu、γ-GABA浓度差异无统计学意义(P＞0.05).结论 异丙酚麻醉对大鼠异相睡眠剥夺时海马内紊乱的Glu和γ-GABA递质有恢复作用,其作用与自然睡眠相似.     

The hypophyseal-testicular axis and sex accessory glands following chemical sympathectomy with guanethidine of pre-pubertal to mature rats

Summary.  Selective chemical sympathectomy of the internal sex organs of prepubertal to mature male Wistar rats was performed by chronic treatment with low doses of guanethidine. Plasma testosterone and luteinizing hormone and the intratesticular level of testosterone were determined. The weight and fructose content of seminal vesicle and ventral prostate were also investigated. The results showed that sympathetic innervation is related to the control of the hypophyseal-testicular axis as well as to the growth and potential secretory activity of the male sex accessory glands.