Changes In Serum Testosterone Levels Research Articles

Testosterone kinetics after proton therapy for low- and intermediate-risk prostate cancer.

237 Background: Evaluate long term changes in serum testosterone levels in patients with low and intermediate risk prostate cancer treated with proton therapy (PT) on two prospective clinical trials. Methods: Between August, 2006 and October, 2007, 171 patients with low and intermediate risk prostate cancer were enrolled and treated on the University of Florida Proton Therapy Institute institutional review board (IRB) approved PR01 and PR02 protocols. Of the 171 patients, 20 were excluded for having received hormonal therapy prior to PT. The pretreatment serum testosterone level was available for 149 of the remaining 151 patients. These 149 patients were included in the present study. Proton doses ranged from 78 Cobalt Gray Equivalent (CGE) to 82 CGE to the prostate using passively scattered protons. No patient underwent pelvic nodal irradiation. Results: The median baseline serum testosterone level was 358ng/dL (range 112 to 791ng/dL). Immediately after completion of PT, median serum testosterone was 365ng/dL which was not significantly different from the pre-PT level (p=0.2039). Subsequent median testosterone levels with associate P-Values are shown in the Table. At no point in the 60 month follow up period was the median serum testosterone value significantly different from the baseline value. Conclusions: Conformal proton therapy to the prostate, as delivered using the University of Florida Proton Therapy Institute PR01 and PR02 protocols, did not appear to significantly affect serum testosterone levels within 60 months after PT. [Table: see text]

Decreased Serum Testosterone Levels in Long-Term Adult Survivors with Fatty Liver after Childhood Stem Cell Transplantation

Fatty liver and male gonadal dysfunction are potential late effects of therapy in adult survivors treated with stem cell transplantation (SCT) in childhood. Obesity and metabolic syndrome also are associated with low serum testosterone levels in the general population. However, the relationship between the degree of fatty liver and changes in serum testosterone levels in adult survivors has not been fully studied. We reviewed the clinical records of 34 male patients who received allogeneic SCT in childhood or adolescence. The median age at SCT was 10.0 years, and the median follow-up after SCT was 15.9 years. All but one patient showed no tendency toward overweight/obesity during the follow-up period. Fatty liver was diagnosed by ultrasound in 15 patients at 4 to 20 years after SCT. Patients who received cranial radiation therapy before SCT were more likely to develop fatty liver and insulin resistance. Moreover, fatty liver was statistically associated with decreased serum testosterone levels, whereas nonfatty liver was not (median, 527 ng/dL [range, 168-944 ng/dL] versus 302 ng/dL [165-698 ng/dL]; P < .0001). Changes in testosterone levels after SCT are affected not only by primary gonadal dysfunction but also by subsequent development or exacerbation of fatty liver.

Disruption of spermatogenesis and differential regulation of testicular estrogen receptor expression in mice after polychlorinated biphenyl exposure

The testicular toxicity of polychlorinated biphenyls (PCBs) has been extensively studied. However, the detailed mechanism is still obscure. In the present study, male C57 mice were treated with different doses of Aroclor 1254 (a commercial PCB mixture) once every 3 days by oral gavage. After exposure to Aroclor 1254 for 50 days, the sperm count decreased in a dose-dependent manner. Cell proliferation and apoptosis are key processes regulating development of the testis, and alterations in these processes may underlie testicular dysgenesis. Our results showed that the germ cell proliferation was inhibited and the apoptosis of the germ cell was induced in a dose-dependent manner after treatment with Aroclor 1254. Although there was no significant change in serum testosterone levels and androgen receptor expression levels after treatment with different dosages of Aroclor 1254, the estradiol levels decreased and the expression of estrogen receptor (ER) β increased in a dose-dependent manner, whereas an elevation of the expression of ERα was only observed in the 50 μg/kg group. The data as a whole suggested that inhibited proliferation and induced apoptosis in germ cells, and a differential regulation of ER, may be involved in the testicular toxicity of PCBs.

Testosterone regulates tight junction proteins and influences prostatic autoimmune responses.

Testosterone and inflammation have been linked to the development of common age-associated diseases affecting the prostate gland including prostate cancer, prostatitis, and benign prostatic hypertrophy. We hypothesized that testosterone regulates components of prostate tight junctions which serve as a barrier to inflammation, thus providing a connection between age- and treatment-associated testosterone declines and prostatic pathology. We examined the expression and distribution of tight junction proteins in prostate biospecimens from mouse models and a clinical study of chemical castration, using transcript profiling, immunohistochemistry, and electron microscopy. We determined that low serum testosterone is associated with reduced transcript and protein levels of Claudin 4 and Claudin 8, resulting in defective tight junction ultrastructure in benign prostate glands. Expression of Claudin 4 and Claudin 8 was negatively correlated with the mononuclear inflammatory infiltrate caused by testosterone deprivation. Testosterone suppression also induced an autoimmune humoral response directed toward prostatic proteins. Testosterone supplementation in castrate mice resulted in re-expression of tight junction components in prostate epithelium and significantly reduced prostate inflammatory cell numbers. These data demonstrate that tight junction architecture in the prostate is related to changes in serum testosterone levels, and identify an androgen-regulated mechanism that potentially contributes to the development of prostate inflammation and consequent pathology.

The combined toxicity of dibutyl phthalate and benzo(a)pyrene on the reproductive system of male Sprague Dawley rats in vivo

Our previous studies revealed more than 100 pollutants, most of which were endocrine disruptors (EDs) in two Chinese rivers, the Jialing and the Yangtze near Chongqing. Most EDs, such as dibutyl phthalate (DBP) and benzo(a)pyrene (BaP), are known to act individually as reproductive toxicants. However, little is known about the combined toxicity of DBP and BaP. In the current study, male Sprague Dawley rats were subchronically exposed to single doses of DBP (250mg/kg), single doses of BaP (5mg/kg) and combined doses of DBP and BaP. Significant adverse effects were observed on the reproductive system, including decreased sperm count, increased production of abnormal sperm, changes in serum testosterone levels and irregular arrangements of the seminiferous epithelium. Biochemical analyses showed that the activities of superoxide dismutase and glutathione peroxidase decreased after exposure to these EDs. Therefore, our data suggest that exposure to DBP and BaP, in either separate or combined doses, can affect the reproductive system of male rats adversely via oxidative stress-related mechanisms. No significant additive effect was observed after combined exposure. These results indicate that exposure to mixtures of EDs have unexpected and elusive effects. Our findings provide preliminary but important data for assessing water safety in China.

2061 GENETIC POLYMORPHISM INFLUENCES INDIVIDUAL VARIATIONS IN SERUM TESTOSTERONE LEVELS IN PROSTATE CANCER PATIENTS TREATED WITH ANDROGEN DEPRIVATION THERAPY

You have accessJournal of UrologyProstate Cancer: Markers I1 Apr 20102061 GENETIC POLYMORPHISM INFLUENCES INDIVIDUAL VARIATIONS IN SERUM TESTOSTERONE LEVELS IN PROSTATE CANCER PATIENTS TREATED WITH ANDROGEN DEPRIVATION THERAPY Shintaro Narita, Kazuyuki Numakura, Takashi Obara, Hiroshi Tsuruta, Mitsuru Saito, Yohei Horikawa, Norihiko Tsuchiya, and Tomonori Habuchi Shintaro NaritaShintaro Narita More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Takashi ObaraTakashi Obara More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Yohei HorikawaYohei Horikawa More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2108AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Individual variations in serum testosterone levels after androgen deprivation therapy (ADT) have been reported. The objectives of this study were to assess changes in serum testosterone levels after administration and cessation of luteinizing hormone-releasing hormone agonist (LHRHa) and to investigate prognostic factors for testosterone recovery including genetic variations in sex steroid-related genes in prostate cancer (PCa) patients treated with ADT. METHODS A total of 26 localized PCa patients treated with ADT and external beam radiotherapy were enrolled. A neoadjuvant maximal androgen blockade was given for 2 months, and LHRHa was continued for 1 year after radiation therapy. Serum testosterone levels were measured every 3 months. Castrate testosterone levels were defined as 50 ng/dL or less. Testosterone recoveries to supracastrate levels and to the normal range were estimated using the Kaplan-Meier method. Prognostic factors for testosterone recovery, including clinical parameters and six single nucleotide polymorphisms in five genes (VDR, SRD5A2, CYP17, CYP19, and GnRHR), were examined. RESULTS At 9 months after LHRHa cessation, serum testosterone levels returned to supracastrate levels in 14 (53.8%) and to the normal range in 10 (38.5%) of the 26 patients. The median duration of serum testosterone recoveries to supracastrate levels was 10.6 months. The duration of testosterone recoveries to supracastrate levels in patients aged≥72 years was significantly longer than that in patients aged <72 years (14.5±2.7 vs. 9.4±0.8 months,p=0.027). Pretreatment serum testosterone levels and LHRHa type were not associated with testosterone recovery. Patients carrying the bb genotype of the BsmI polymorphism in VDR had a significantly longer testosterone recovery time than that taken by those carrying the Bb genotype (12.0±2.0 vs. 8.2±0.7 months, p=0.045). CONCLUSIONS Variations in the testosterone recovery after LHRHa cessation were found in PCa patients treated with LHRHa followed by external beam radiotherapy. Older age and the bb genotype of the BsmI polymorphism in VDR influenced the slow testosterone recovery in patients with PCa. Akita, Japan© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e801 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shintaro Narita More articles by this author Kazuyuki Numakura More articles by this author Takashi Obara More articles by this author Hiroshi Tsuruta More articles by this author Mitsuru Saito More articles by this author Yohei Horikawa More articles by this author Norihiko Tsuchiya More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Role of FSH in regulating testicular germ cell transformations in the rat: a study using DNA flow cytometry.

The role of FSH in regulating testicular germ cell transformations during initiation and maintenance of spermatogenesis in the pubertal and adult rat has been studied using DNA flow cytometry (FCM). The cell types were quantified on the basis of their DNA content using DNA specific fluorochrome DAPI (4,6-diamidino phenylindole). Pubertal (30-d old) and adult (100-d old) rats were deprived of endogenous FSH support for 10 d by daily injection (200 microliters d-1) of a characterized FSH antiserum; the control group received an equivalent volume of normal rat serum. FSH deprivation did not lead to any change in serum testosterone levels. The relative proportion of testicular germ cells in the FSH deprived pubertal rat showed a 90% reduction in 1C (round spermatids) and 260% and 90% increase in 2C (spermatogonia) and 4C (spermatocytes) cells respectively. While the overall conversion of 2C to 1C (1C:2C ratio) was reduced by 98%, the transformation of 2C to 4C (4C:2C ratio) and 4C to 1C (meiotic division 1C:4C ratio) was inhibited by 43% and 93% respectively. In the FSH-deprived adult rat the overall conversion of 2C to 1C was reduced by 26% (P < 0.05) only. The 2C and 4C population of cells increased by 47% and 97% respectively (P < 0.025) and the 4C:2C ratio by 47% (P < 0.05). While the meiotic division (1C:4C ratio) was reduced by 54% (P < 0.001), the post-meiotic differentiation of round spermatids to elongate-spermatids (HC:1C) was inhibited by 68% (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of Bilateral and Left Varicocelectomy in Infertile Men With Left Clinical and Right Subclinical Varicoceles: A Comparative Study

To determine whether it is necessary to perform bilateral varicocelectomy (BV) in infertile men with left clinical and right subclinical varicoceles by comparing the outcomes of BV with those of left varicocelectomy (LV) in these patients. A total of 104 infertile men with left clinical and right subclinical varicoceles were randomly divided into 2 groups: BV (n = 51) and LV (n = 53). Both BV and LV were performed using a retroperitoneal approach with ligation of the dilated internal spermatic veins. The sperm concentration, sperm motility, normal morphology, serum testosterone level, bilateral testicular volume, and spontaneous pregnancy rate were measured pre- and postoperatively. Statistical analysis was performed using analysis of variance and the chi(2) test, with significance determined by P < .05. The patients in the 2 groups had comparable preoperative age, partner age, sperm concentration, sperm motility, normal morphology, left varicocele grade, serum testosterone level, and bilateral testicular volume (P > .05). Both BV and LV resulted in significant increases in sperm concentration, sperm motility, and normal morphology (P < .05). No significant changes in serum testosterone level or bilateral testicular volume were observed after varicocelectomy in the 2 groups (P > .05). No significant differences were found in the postoperative sperm concentration, sperm motility, normal morphology, bilateral testicular volume, serum testosterone level, and spontaneous pregnancy rate between the 2 groups (P > .05). These findings suggest that no benefit is realized with BV compared with LV in infertile men with left clinical and right subclinical varicoceles.

The decline of serum testosterone levels in community-dwelling men over 70 years of age: descriptive data and predictors of longitudinal changes

This study was designed to assess longitudinal changes in serum testosterone levels, explore relationships with aging, genetic-, health-, and lifestyle-related factors, and investigate predictors of changes in healthy elderly men. Population-based, longitudinal, 4-year observational study in 221 community-dwelling men aged 71-86 years at baseline. Hormone levels assessed by immunoassay, anthropometry, questionnaires on general health, and genetic polymorphisms. Predictors of changes in testosterone levels explored using linear mixed-effects modeling for longitudinal analyses. Total testosterone (TT), free testosterone, and bioavailable testosterone (BioT) levels decreased with aging, decreases in BioT being most marked. No changes in sex hormone-binding globulin (SHBG) or estradiol (E(2)), while LH and FSH levels increased during follow-up. Subjects who gained weight displayed a greater decline in TT levels, mainly due to decreasing SHBG levels. However, baseline body composition was not predictive of subsequent changes in testosterone levels. Baseline E(2) (P=0.023 to 0.004), LH (P=0.046 to 0.005), and FSH (P<0.002) levels were independently positively associated with a faster decline in testosterone fractions, although only FSH remained significant when adjusting for baseline testosterone (P=0.041-0.035). Carriers of a 'TA' haplotype of the estrogen receptor alpha gene (ER alpha) PvuII and XbaI polymorphisms displayed a slower decline of TT and BioT (P=0.041-0.007). In elderly men with already low serum testosterone levels, a further decline was observed, independent of baseline age. The identification of FSH levels as a predictor of this decline appears to reflect the testicular mechanisms of aging-related changes in testosterone production, whereas associations with E(2) and ER alpha polymorphisms are suggestive of estrogen-related processes, possibly related to changes in the neuroendocrine regulation of testosterone production.

Disruption of Growth Hormone Signaling Retards Prostate Carcinogenesis in the Probasin/TAg Rat

We asked whether down-regulation of GH signaling could block carcinogenesis in the Probasin/TAg rat, a model of aggressive prostate cancer. The Spontaneous Dwarf rat, which lacks GH due to a mutation (dr) in its GH gene, was crossed with the Probasin/TAg rat, which develops prostate carcinomas at 100% incidence by 15 wk of age. Progeny were heterozygous for the TAg oncogene and homozygous for either the wild-type GH gene (TAg/Gh(+/+)) or the dr mutation (TAg/Gh(dr/dr)). Prostate tumor incidence and burden were significantly reduced, and tumor latency was delayed in TAg/Gh(dr/dr) rats relative to TAg/Gh(+/+) controls. At 25 wk of age, loss of GH resulted in a 20 and 80% decrease in the area of microinvasive carcinoma in the dorsal and lateral lobes, respectively. By 52 wk of age, invasive prostate adenocarcinomas were observed in all TAg/Gh(+/+) rats, whereas the majority of TAg/Gh(dr/dr) did not develop invasive tumors. Suppression of carcinogenesis could not be attributed to alterations in prostate expression of TAg or androgen receptor or changes in serum testosterone levels. As carcinogenesis progressed in TAg/Gh(+/+) rats, prostate GHR mRNA and protein expression increased significantly, but prostate IGF-I receptor mRNA and protein levels dropped. Furthermore, serum IGF-I and prostate IGF-I levels did not change significantly over the course of carcinogenesis. These findings suggest that GH plays a dominant role in progression from latent to malignant prostate cancer driven by the powerful probasin/TAg fusion gene in rats and suggest that GH antagonists may be effective at treating human prostate cancer.

Effect of Testosterone Replacement Therapy on Prostate Tissue in Men With Late-Onset Hypogonadism

Prostate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men. To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels. Randomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004. Participants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months. The primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression. Of the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL [9.8 nmol/L]; median at 6 months, 640 ng/dL [22.2 nmol/L]) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU [Clusterin]), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor. These preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study. Trial Registration clinicaltrials.gov Identifier: NCT00161304.

A phase II study of imatinib mesylate in prostate cancer patients with evidence of biochemical relapse following definitive radical retropubic prostatectomy or radiation therapy

3092 Background: Biochemical recurrence of prostate cancer after definitive or salvage local therapy in the absence of metastatic disease represents a group of men well suited for a novel therapeutic intervention. Imatinib mesylate (Gleevec) is a protein-tyrosine kinase inhibitor which has previously been tested in men with androgen-independent and metastatic prostate cancer. This phase II study was undertaken to determine the safety and efficacy of imatinib mesylate in men with biochemical relapse of non-metastatic, androgen-sensitive prostate cancer following local therapy. Patients and Methods: Twenty-seven patients were treated with imatinib mesylate 400mg twice daily for 12 months or until evidence of disease progression or dose limiting toxicity. All patients had evidence of biochemical progression with a rising PSA after definitive radiation therapy, prostatectomy, or prostatectomy and salvage radiation therapy. Three patients (11%) completed less than 4 weeks of therapy and were not evaluable. Results: Of the 24 patients evaluated for a biochemical response, six patients (22%) demonstrated a stable PSA over the course of treatment; two patients (7%) experienced a partial response to treatment as defined by a PSA decline of greater than 50% for at least 4 weeks duration. Duration of response in these two patients was 5 months and 12 months. Sixteen patients (59%) demonstrated progressive disease as defined by a 25% or greater increase in PSA above the baseline value at study entry. There was no association between overall PSA response and changes in serum testosterone level. The proportion of patients achieving a partial response in PSA while on therapy did not significantly differ from the null rate of 5% using a two-sided exact binomial test (P=0.394; 95% CI 0.9% - 24.3%). There was no irreversible NIH-CTC Grade 3 or 4 toxicities. Grade 3 and 4 toxicity included leukopenia (3.7%), elevation in SGOT (7.4%) and SGPT (7.4%), and rash (18.5%). Conclusions: Imatinib mesylate delivered at a dose of 400mg twice daily is associated with acceptable toxicity and limited ability to confer a PSA response in this patient population. No significant financial relationships to disclose.

Associations between Serum Testosterone Fall and Cognitive Function in Prostate Cancer Patients

Data on the association between cognition and testosterone levels in elderly men are inconclusive. Androgen deprivation therapy is commonly used in the treatment of prostate cancer with the aim of achieving castration levels of serum testosterone. The study group comprised 26 elderly men (mean age 65 years) with newly diagnosed prostate cancer. Cognitive testing was done at baseline and at 6 and 12 months on androgen deprivation therapy. Cognitive performances were evaluated using verbal, visuomotor, and memory tests as well as tests of processing speed and attention. Castration levels of testosterone were achieved in all patients by 6 months. Significant associations between cognitive performances and testosterone decline were documented: visuomotor slowing, slowed reaction times in some attentional domains including working memory and impaired hit rate in a vigilance test, impaired delayed recall and recognition speed of letters, but improvement in object recall. The results suggest selective associations between testosterone decline and cognition. Documentation of cognitive performance with changes in serum testosterone levels has substantial implications for informed patient support in prostate cancer.

MicroPET assessment of androgenic control of glucose and acetate uptake in the rat prostate and a prostate cancer tumor model

PET has been used to monitor changes in tumor metabolism in breast cancer following hormonal therapy. This study was undertaken to determine whether PET imaging could evaluate early metabolic changes in prostate tumor following androgen ablation therapy. Studies were performed comparing two positron-emitting tracers, 18F-FDG and 11C-acetate, in Sprague-Dawley male rats to monitor metabolic changes in normal prostate tissue. Additional studies were performed in nude mice bearing the CWR22 androgen-dependent human prostate tumor to evaluate metabolic changes in prostate tumor. In rats, for the androgen ablation pretreatment, 1 mg diethylstilbestrol (DES) was injected subcutaneously 3 and 24 hours before tracer injection. For androgen pretreatment, 500 μg dihydrotestosterone (DHT) was injected intraperitoneally 2 and 6 hours before tracer injection. The rats were divided into three groups, Group A (no-DES, no-DHT, n = 18), Group B (DES, no-DHT, n = 18) and Group C (DES, DHT, n = 18). In each group, 10 animals received 18F-FDG, whereas the remaining eight animals were administered 11C-acetate. Rats were sacrificed at 120 min post-injection of 18F-FDG or 30 min post-injection of 11C-acetate. Pretreatment of the mouse model using DHT (200 μg of DHT in 0.1 mL of sunflower seed oil) or DES (200 μg of DES in 0.1 mL of sunflower seed oil) was conducted every 2 days for one week. Mice were imaged with both tracers in the microPET scanner (Concorde Microsystems Inc.). DES treatment caused a decrease in acetate and glucose metabolism in the rat prostate. Co-treatment with DHT maintained the glucose metabolism levels at baseline values. In the tumor bearing mice, similar effects were seen in 18F-FDG study, while there was no significant difference in 11C-acetate uptake. These results indicate that changes in serum testosterone levels influence 18F-FDG uptake in the prostate gland, which is closely tied to glucose metabolism, within 24 hours of treatment and in the prostate tumor within 1 week. These early metabolic changes could enable monitoring metabolic changes in prostate tumor following treatment by imaging using 18F-FDG PET. Further studies are needed to clarify the reason for the insensitivity of 11C-acetate for measuring metabolic change in prostate tumor.

No androgenic/anti-androgenic effects of bisphenol-A in Hershberger assay using immature castrated rats

Several studies have demonstrated that bisphenol A (BPA) exhibited weak estrogenic activity in the 3-day uterotrophic assay using ovariectomized (OVX) and immature rats (Toxicol. Lett. 115 (2000) 231; Regul. Toxicol. Pharmacol. 32 (2000) 118; J. Toxicol. Sci. 26 (2001) 111) and BPA also possessed anti-androgenic activity in in vitro yeast based assays (J. Endocrinol. 158 (1998) 327). To investigate anti-androgenic effects of BPA. a rodent Hershberger assay was carried out using immature Sprague–Dawley male rats. An androgen agonist, testosterone (0.4 mg/kg per day), was administered for 7 consecutive days by subcutaneous (s.c.) injection as a positive control. Additionally, a pure androgen antagonist, flutamide (1, 5. 10 mg/kg per day. oral) was co-administered with testosterone (0.4 mg/kg per day s.c.). BPA was also administered orally with or without testosterone (0.4 mg/kg per day, s.c.) for 7 consecutive days. In the testosterone treated groups, glans penis, seminal vesicles, ventral prostate, and levator ani plus bulbocavernosus muscles (LABC) weights were significantly increased compared with control. However. flulamide dose-dependently inhibited the testosterone-induced re-growth of seminal vesicles, ventral prostate, and LABC, with a significant decrease at flutamide 1.0 mg/kg and above ( P<0.05). Serum LH levels were also significantly increased (5 mg/kg and above, P<0.05), but no changes in serum testosterone levels. In contrast, BPA had no effects on the re-growth of seminal vesicles, ventral prostate and LABC induced by testosterone, and no significant differences were observed in serum LH and testosterone levels. In summary, the Hershberger assay could be a sensitive method for detecting androgenic or anti-androgenic chemicals, but BPA did not exhibit any androgenic or anti-androgenic activities in Hershberger assay.

Loss of gender difference in serum leptin levels and its slow recovery after successful surgery for Leydig cell tumours in two virilized females

One of the factors that predicts serum leptin levels is gender. It has been shown that sex steroid hormones, in particular testosterone, play an important role in the regulation of serum leptin levels. We had the opportunity to examine the effects of acute and chronic changes in serum testosterone levels on serum leptin concentrations in two virilized females harbouring testosterone-secreting ovarian tumours, before and after curative surgery. Chronically elevated basal testosterone levels (46 nmol/l) were associated with suppressed serum leptin levels (1.46 microg/l and 2.56 microg/l) vs. 12 age- and BMI-matched healthy subjects 9.89 +/- 0.64 microg/l. Leptin levels were determined from pooled serum samples assayed by commercial radioimmunoassay. High testosterone levels abolished the well known sexual dimorphism of serum leptin levels. Two weeks after curative resection of these tumours serum leptin levels were unaltered and started to increase progressively after one month. One patient received parenteral conjugated oestrogens while the other resumed spontaneous menstrual cycles. Three months after curative surgery obvious changes in body composition were registered (DEXA). Six months later further rise in serum leptin concentrations occurred without further changes in body composition. In conclusion, leptin levels did not change in spite of rapid changes in the steroid milieu, but in the long term increase in body fat stores, new steroid milieu and maybe other factors are important determining factors of serum leptin levels.

MORPHOLOGICAL ALTERATIONS AND INTRATUBULAR LIPID INCLUSIONS AS INDICATIVE OF SPERMATOGENIC DAMAGE IN CIMETIDINE-TREATED RATS

Doses of cimetidine (50 mg/kg b/w) were administered to adult male Wistar rats over 52 consecutive days. Besides plasma testosterone levels, morphological and morphometric aspects of the seminiferous tubules as well as histochemical analysis of the lipid content by oil red O were emphasized. Abnormal tubules exhibiting disorganization of their cellular association, loss of germ cells, and multinucleated giant spermatids were usually found. Significant reductions of testis weight and tubular diameter at specific stages (VII-IX), as well as lack of contact between Sertoli cells and spermatids in tubules at stage IX, suggest a possible interference of cimetidine on the histoarchitecture of the seminiferous epithelium. The dense concentration of lipid inclusions in tubules at postspermiation stages indicates phagocytosis and degradation of germ cells. Since no change in serum testosterone levels was verified in cimetidine-treated rats, the authors could not exclude the possibility that besides an antiandrogenic effect, other biochemical factors necessary for normal spermatogenesis could be involved in the testicular alterations.

The contribution of hepatic inactivation of testosterone to the lowering of serum testosterone levels by ketoconazole.

Hepatic biotransformation processes can be modulated by chemical exposure and these alterations can impact the biotransformation of endogenous substrates. Furthermore, chemically mediated alterations in the biotransformation of endogenous steroid hormones have been implicated as a mechanism by which steroid hormone homeostasis can be disrupted. The fungicide ketoconazole has been shown to lower serum testosterone levels and alter both gonadal synthesis and hepatic inactivation of testosterone. The present study examined whether the effects of ketoconazole on the hepatic biotransformation of testosterone contribute to its lowering of serum testosterone levels. Results also were used to validate further the use of the androgen-regulated hepatic testosterone 6alpha/15alpha-hydroxylase ratio as an indicator of androgen status. Male CD-1 mice were fed from 0 to 160 mg/kg ketoconazole in honey. Four h after the initial treatment, serum testosterone levels, gonadal testosterone secretion, and hepatic testosterone hydroxylase activity decreased, and the hepatic testosterone 6alpha/15alpha-hydroxylase ratio increased in a dose-dependent manner. Immunoblot analysis indicated that the transient decline in hepatic biotransformation was not due to reduced P450 protein levels. Rather, hepatic testosterone biotransformation activities were found to be differentially susceptible to direct inhibition by ketoconazole. Differential inhibition was also responsible for the increase seen in the 6alpha/15alpha-hydroxylase ratio. The changes in serum testosterone levels could be explained by decreased gonadal synthesis of testosterone and were not impacted by decreased hepatic biotransformation of testosterone. These results demonstrate that changes in the hepatic hydroxylation of testosterone by ketoconazole, and perhaps other chemicals, have little or no influence serum testosterone levels.

The presence of the 21-hydroxylase deficiency carrier status in hirsute women: phenotype-genotype correlations

Objective: To determine the role of heterozygosity for mutations in the 21-hydroxylase gene ( CYP21) in the pathogenesis of hyperandrogenism. Design: Controlled clinical study. Setting: Tertiary care institutional hospital. Patient(s): Forty hirsute women and 13 healthy control women. Intervention(s): The source of androgen excess was determined by the changes in serum testosterone levels in response to a single 3.75-mg IM dose of triptorelin. Main Outcome Measure(s): CYP21 molecular genetic analysis and serum 17-hydroxyprogesterone levels. Result(s): Eight patients and one control were heterozygous carriers of CYP21 mutations. Two patients with adrenal hyperandrogenism and one patient with ovarian hyperandrogenism, who carried the V281L mutation had an increased ACTH-stimulated 17-hydroxyprogesterone level (>4.1 ng/mL) that persisted during gonadal suppression. Another patient with adrenal hyperandrogenism carried the V281L mutation, and her ACTH-stimulated 17-hydroxyprogesterone level was elevated only during gonadal suppression. Four patients (three with idiopathic hirsutism, one with ovarian hyperandrogenism) and one control were carriers of CYP21 mutations typically associated with classic congenital adrenal hyperplasia but had normal basal and ACTH-stimulated 17-hydroxyprogesterone levels. Nine patients without CYP21 mutations had increased ACTH-stimulated 17-hydroxyprogesterone levels; these decreased to normal in six of the patients during gonadal suppression. Conclusion(s): The response of serum 17-hydroxyprogesterone to ACTH does not predict CYP21 carrier status. No clear concordance was found between the CYP21 genotype and the functional origin of androgen excess.

Effects of thyroid hormone (thyroxine) and testosterone on hepatic 11beta-hydroxysteroid dehydrogenase mRNA and activity in pubertal hypothyroid male rats.

To investigate the effects of thyroid hormone and testosterone on 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), we measured changes in hepatic 11beta-dehydrogenase activity and its mRNA levels in pubertal methimazole (MMI)-induced hypothyroid male rats following treatment with thyroxine ([T4] 50 microg/kg/d) or testosterone (250 microg/d) for 14 days. Hypothyroidism in male rats markedly reduced hepatic 11beta-HSD1 mRNA levels and serum testosterone concentrations (P < .01). Subcutaneous injection of T4 in the hypothyroid rats significantly (P < .01) increased hepatic 11beta-HSD1 mRNA to approximately normal levels and simultaneously increased serum testosterone levels. However, the same daily dose of T4 administered to castrated male hypothyroid rats for 14 days did not elevate hepatic 11beta-HSD1 activity. Treatment with testosterone for 14 days in castrated hypothyroid male rats and rats without gonadectomy significantly (P < .01) increased the enzyme activity without administration of T4. Variations in hepatic 11beta-HSD1 activity were demonstrated to be accompanied by changes in serum testosterone levels in the rats following alteration of the thyroid hormone state. These results suggest that the effect of T4 in increasing the subnormal 11beta-HSD1 gene expression in hypothyroid male rats is mediated by its ability to increase testosterone production in these rats, because in castrated hypothyroid rats, T4 does not elevate 11beta-HSD1 gene expression.