Etsuko Isahaya

Serum prostate-specific antigen levels reflect the androgen milieu in patients with localized prostate cancer receiving androgen deprivation therapy: Tumor malignant potential and androgen milieu†‡

Although androgen deprivation therapy (ADT) has a marked impact on the androgen milieu in vivo and outcomes of prostate cancer (PCa), it remains unclear which parameters reflect the androgen milieu during ADT or whether the milieu is associated with PCa aggressiveness.

Bone metabolic disorder in patients with prostate cancer receiving androgen deprivation therapy (ADT): impact of ADT on the growth hormone/insulin‐like growth factor‐1/parathyroid hormone axis

Although androgen deprivation therapy (ADT) has been associated with bone loss in patients with prostate cancer, its mechanism remains unclear. The growth hormone (GH)/insulin‐like growth factor‐1 (IGF‐1)/parathyroid hormone (PTH) axis plays a critical role in bone synthesis, but its activity during ADT is also unknown.

Insulin-like growth factor-1 is associated with regulation of the luteinizing hormone production in men receiving androgen deprivation therapy with gonadotropin-releasing hormone analogues for localized prostate cancer.

BACKGROUND Luteinizing hormone (LH) during androgen-deprivation therapy (ADT) with gonadotropin-releasing hormone analogues (GnRHa) has been thought to be biologically inactive, and the regulation of LH during ADT with GnRHa is thus unknown. Insulin-like growth factor-1 (IGF-1) is involved in the regulation of cell proliferation and differentiation, and IGF-1 production in the liver is dependent on growth hormone (GH) secretion from the anterior pituitary. Despite the presence of IGF-1 receptors in the gonadotroph, associations between the GH/IGF-1 and pituitary-gonadal axes, e.g., whether IGF-1 elicits the LH secretion, remain unclear. METHODS Seventy-one patients with localized prostate cancer, who received ADT with GnRHa, were prospectively studied based on their blood samples before treatment and after ADT for 6 months. We employed highly sensitive assays for measurement of serum testosterone (electrochemiluminescence immunoassay), GH/IGF-1 (radioimmunoassay), adrenocorticotropic hormone (ACTH: immunoradiometric assay), LH (chemiluminescent immunoassay), and dehydroepiandrosterone sulfate (DHEA-S: chemiluminescent enzyme immunoassay). RESULTS No correlation was noted between the pretreatment LH and IGF-1 levels; after ADT, the serum LH level was closely correlated with the IGF-1 concentration [Spearmans correlation coefficient (rs) = 0.370, P = 0.001]. The serum levels of androgens and gonadotropins reduced following ADT (P < 0.001 in all). The serum IGF-1 level increased (22 ± 6 nmol/L) compared with that at the baseline (19 ± 5 nmol/L) (P < 0.001), but no change was observed in the serum GH concentration between before and after ADT (1.4 ± 2.3 vs. 0.9 ± 0.9 μg/L, respectively, P = 0.691). The serum testosterone level was not correlated with the LH level either before or after ADT. The testosterone and DHEA-S levels after ADT were correlated with ACTH concentration (rs = 0.367, P = 0.002 and rs = 0.354, P = 0.002, respectively). We did not identify any correlations between the serum IGF-1 concentration and Gleason score, PSA value, or androgen levels. CONCLUSIONS During ADT with GnRHa, IGF-1 possibly promotes LH production, although its role is unclear. Associations among pituitary-gonadal, pituitary-adrenal, and GH/IGF-1 axes represented by IGF-1-mediated LH secretion and ACTH-mediated androgen synthesis are of interest, since both prostate epithelium proliferation and male anabolic activity are involved in these 3 axes. Assessment of oncologic outcomes is warranted for their significance in patients with prostate cancer.

Altered association of interleukin-6 with sex steroids in lipid metabolism disorder in men with prostate cancer receiving androgen deprivation therapy.

Interleukin‐6 produced in adipose tissue plays a role in lipid metabolism, and also interacts with sex steroids. This study was performed to elucidate the mechanism of lipid metabolism disorder during androgen deprivation therapy (ADT) in terms of the association of interleukin‐6 with sex steroids.

Clinical Feature of Men Who Benefit from Dose Escalation of Naftopidil for Lower Urinary Tract Symptoms: A Prospective Study

Objectives. To examine the feature of men who benefit from dose escalation of naftopidil for lower urinary tract symptoms (LUTSs). Methods. Based on the IPSS, men reporting LUTS were prospectively studied using 50 mg/day of naftopidil for the first 4 weeks; satisfied patients continued its 50 mg/day (n = 11), and those reporting unsatisfactory improvement received its 75 mg/day (n = 35) for the next 4 weeks. Results. The 75 mg group showed improvement in the total IPSS and QOL score in a dose-dependent manner (at 4 weeks: P < .001, at 4 weeks versus 8 weeks: P < .05). In the 50 mg group, both scores reduced at 4 weeks, thereafter unchanged. The baseline slow stream score alone was higher in the 75 mg group (P = .013). The rate of change in the QOL score during the initial 4 weeks (ΔQOL) and Δnocturia was smaller in the 75 mg group (P < .05). Conclusions. Men with high slow stream score and unsatisfactory improvement in nocturia may benefit from dose escalation of naftopidil.

Adrenocorticotropic Hormone is Involved in Regulation of Androgen Synthesis in Men Receiving Androgen Deprivation Therapy for Localized Prostate Cancer

PURPOSE We elucidated the regulatory mechanism of adrenal androgen synthesis and examined the influence of pituitary-adrenal axis activity on prostate specific antigen during androgen deprivation therapy. MATERIALS AND METHODS A total of 72 patients with localized prostate cancer were prospectively studied based on blood samples before and after androgen deprivation therapy for 6 months. Serum pituitary hormones, androgens and prostate specific antigen were measured using highly sensitive assays. RESULTS After androgen deprivation therapy serum levels of luteinizing hormone, follicle-stimulating hormone, testosterone, dehydroepiandrosterone sulfate, androstenedione and prostate specific antigen decreased compared with those at the baseline (all values p <0.001). No difference was noted between serum levels before and after androgen deprivation therapy in growth hormone (p = 0.098) and adrenocorticotropic hormone (p = 0.101). Each serum level of luteinizing hormone, follicle-stimulating hormone and growth hormone after androgen deprivation therapy was not correlated with the serum levels of androgens or prostate specific antigen. The serum adrenocorticotropic hormone level after androgen deprivation therapy was correlated with the serum levels of testosterone (p = 0.002), dehydroepiandrosterone sulfate (p = 0.002), androstenedione (p = 0.006) and prostate specific antigen (p <0.001). Serum dehydroepiandrosterone sulfate and androstenedione levels were also correlated with serum prostate specific antigen (p <0.001 and p = 0.002, respectively). CONCLUSIONS In patients treated with androgen deprivation therapy the pituitary-adrenal axis mediated by adrenocorticotropic hormone has a central role in the regulation of androgen synthesis. Serum adrenocorticotropic hormone and adrenal androgen concentrations were correlated with the posttreatment prostate specific antigen. Adrenocorticotropic hormone mediated androgen synthesis is a potential target for advanced androgen deprivation therapy.

Deficiency in androgens and upregulation of insulin-like growth factor-1 are involved in high bone turnover in men receiving androgen deprivation therapy for prostate cancer

OBJECTIVE This study was performed to elucidate the mechanism of high bone turnover during androgen deprivation therapy (ADT) in terms of osteogenic endocrine activity by testosterone, adrenal androgens, and insulin-like growth factor-1 (IGF-I), and to identify markers reflecting the bone mineral density (BMD) during ADT. DESIGN BMD and samples of blood and urine were studied before and after 6months of ADT in 70 patients with localized prostate cancer. RESULTS Before ADT, serum free-testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and IGF-I levels were correlated with BMD (rs=0.344, p=0.004; rs=0.264, p=0.027; rs=0.329, p=0.005; rs=0.300, p=0.012, respectively). The serum IGF-I level was independently correlated with the pretreatment BMD (Multivariate p=0.001). These relationships disappeared after ADT (p=0.519, 0.316, 0.116, and 0.597, respectively). After ADT, serum levels of free-testosterone decreased (7.9 to 0.2pg/mL), and DHEA-S and androstenedione were also reduced (3.6 to 2.3μmol/L and 5.6 to 2.9nmol/L, respectively) (p<0.001 in all). In contrast, IGF-I levels were elevated after ADT by 11.6% (19.9 to 22.3nmol/L, p<0.001). Delta-values of IGF-I (post- minus pretreatment levels, mean: +2.2, ranged between -7.1 and +15.3) were inversely correlated with the pretreatment (rs=-0.333 p=0.005) and post-treatment (rs=-0.408, p=0.001) BMD. After ADT, the serum IGF-I level was closely correlated with the serum level of the bone formation marker bone-specific alkaline phosphatase (BAP) (rs=0.328, p=0.006), and delta-IGF-I and delta-BAP showed a close positive correlation (rs=0.388, p=0.001). The post-treatment BMD was correlated only with the urine deoxypyridinoline (DPD) concentration (rs=-0.302, p=0.024) among the bone formation/resorption markers including serum/urine N-telopeptide. CONCLUSIONS Serum IGF-I levels increased during ADT in men with a low BMD. Coupled with reduced androgen levels, elevated IGF-I levels, which were positively correlated with BAP during ADT, possibly explain the mechanism of ADT-related high bone turnover. The increase of IGF-I is more prominent in men whose BMD is already low at the baseline, and urine DPD might be a marker that reflects BMD during ADT.

Efficacy of Clean Intermittent Catheterization for Urinary Incontinence in Children with Neurogenic Bladder Dysfunction Secondary to Myelodysplasia.

Objectives: To evaluate the efficacy of clean intermittent catheterization for urinary incontinence in myelodysplastic children.