Arterial stiffness is increased in young women with endometriosis.

Endometriosis is a chronic gynaecological disorder that is accompanied by inflammation and oxidative stress. Atherosclerosis has a long subclinical progression in arteries of children and young adults decades before overt clinical manifestations of the disease. In this study, we determined arterial stiffness by measuring brachial-ankle pulse wave velocity (baPWV) in women with endometriosis to assess the presence of subclinical atherosclerosis. We also measured markers of inflammation and oxidative stress in women with endometriosis. baPWV in women with endometriosis aged over 30 years was significantly higher than that in women without endometriosis aged over 30 years (p < 0.05), but not in women aged less than 30. Serum high-sensitivity C-reactive protein level in women with endometriosis was significantly higher than that in controls (p < 0.05). Young women with endometriosis show significantly increased arterial stiffness, suggesting that women with endometriosis need to be cautious of the future onset of atherosclerosis.

The type 2 corticotrophin-releasing hormone receptor mediates orexin A-induced luteinising hormone suppression in ovariectomised rats.

Orexins are thought to be regulatory factors of the arousal and sleep patterns. They also affect immune, feeding, autonomic and neuroendocrine systems. We have previously shown that intracerebroventricular (i.c.v.) injection of orexin decreases pulsatile luteinising hormone (LH) secretion in ovariectomised (OVX) rats. However, the details of this mechanism have not been fully examined. Intracerebroventricular injection of orexin A also stimulates corticotrophin-releasing hormone (CRH) systems, which have been implicated in the stress-induced suppression of reproductive function. In the present study, we investigated the role of CRH systems in orexin-induced LH suppression. OVX rats were implanted with i.c.v. and intravenous (i.v.) cannulae. After i.c.v. injection of orexin and/or CRH receptor antagonists, blood samples were collected through the i.v. cannula at 6-min intervals for 120 min for LH measurement. Intracerebroventricular injection of orexin A or B (3 nmol/2.5 microl) suppressed pulsatile LH secretion. Coadministration of orexin A and alpha-helical corticotrophic-releasing factor (CRF), a nonselective CRH receptor antagonist (13 nmol/2.5 microl), or astressin(2)B, a selective type2 (CRH-R2) CRH receptor antagonist (28 nmol/2.5 microl), partly restored pulsatile LH secretion. Orexin B-induced LH suppression was not restored by alpha-helical CRF. In addition, i.c.v. injection of orexin A increased CRH and urocortin II (UcnII), but not Ucn mRNA levels, in the hypothalamus. These findings suggest that CRH-R2 mediates orexin A-induced LH suppression and it is possible that CRH and UcnII in the hypothalamus are involved in this pathway.

beta-Microseminoprotein/prostatic secretory protein is a member of immunoglobulin binding factor family.

Human seminal plasma contains a factor that binds human IgG, designated as immunoglobulin binding factor (IgBF). Under reducing condition IgBF interacts with anti-Leu-11b, a murine monoclonal antibody raised against human FcgammaRIII/CD16. IgBF shows no binding activity under non-reducing condition. Three components having IgBF activity were separated by HPLC and their amino acid sequences determined. The main IgBF showed structural identity to beta-microseminoprotein (beta-MSP), prostatic secretory protein of 94 amino acids (PSP94) and beta-inhibin. The slight variation in the reported sequences of these proteins has been attributed to analytical error. In the present study the molecular masses of main IgBF and beta-MSP/PSP94 were found to be identical by mass spectrometry. In addition, a large component of IgBF and a shorter beta-MSP consisting of 93 amino acids were identified. The binding of beta-MSP for human IgG and anti-Leu-11b antibody is demonstrable only under reducing condition, determined by Western blot analysis. The present data clearly show that IgBF is a family composed of at least three isoforms. One of the members is beta-MSP/PSP94. This family should be designated as IgBF.

Differential immunolabeling for electron microscopy of diverse peptidergic neurons.

We describe a simple and reliable method for differential immunolabeling of pre- and post-synaptic signal peptides at the ultrastructural level. Hypothalamic tissues of rats, including the suprachiasmatic nucleus, were cut on a Vibratome. Visualization of the immunolabeling of somatostatin (SRIH) and vasoactive intestinal polypeptide (VIP) was performed with avidin-biotin-peroxidase-diaminobenzidine (DAB). The end product of the DAB to VIP was further silver-intensified in a physical processing using silver nitrate, and the silver grains were finally substituted for gold. DAB-labeled SRIH fibers synapse on gold-labeled VIP perikarya and dendrites in the suprachiasmatic nucleus.

Serum osteoprotegerin/osteoclastogenesis-inhibitory factor during pregnancy and lactation and the relationship with calcium-regulating hormones and bone turnover markers.

Pregnancy and lactation induce dynamic changes in maternal bone and calcium metabolism. A novel cytokine termed osteoprotegerin (OPG)/osteoclastogenesis-inhibitory factor (OCIF) was recently isolated; this cytokine inhibits osteoclast maturation. To define the effects of pregnancy and lactation on circulating OPG/OCIF in mothers, we studied the changes in the levels of OPG/ OCIF as well as those of calcium-regulating hormones and biochemical markers of bone turnover in the maternal circulation during pregnancy (at 8-11 weeks, at 22-30 weeks, at 35-36 weeks and immediately before delivery) and lactation (at 4 days and at 1 month postpartum). Serum intact parathyroid hormone levels did not change and were almost within the normal range in this period. In contrast, serum 1,25-dihydroxyvitamin D levels increased with gestational age and were above the normal range during pregnancy. After delivery, they fell rapidly and significantly (P<0.01) to the normal range. The levels of serum bone-specific alkaline phosphatase, one of the markers of bone formation, increased with gestational age. After delivery, these levels were further increased at 1 month postpartum. The levels at 1 month postpartum were significantly higher than those at 8-11 and 22-30 weeks of pregnancy (P<0.01 and P<0.05 respectively). The levels of serum C-terminal telopeptides of type I collagen, one of the markers of bone resorption, did not change during pregnancy. After delivery, they rapidly and significantly (P<0.01) rose at 4 days postpartum, and had then fallen by 1 month postpartum. Circulating OPG/OCIF levels gradually increased with gestational age and significantly (P<0.01) increased immediately before delivery to 1.40+/-0.53 ng/ml (means+/-S.D.) compared with those in the non-pregnant, non-lactating controls (0.58+/-0.11 ng/ml). After delivery, they fell rapidly to 0.87+/-0.27 ng/ml at 4 days postpartum and had fallen further by 1 month postpartum. These results suggest that the fall in OPG/OCIF levels may be partially connected with the marked acceleration of bone resorption after delivery.

Postmenopausal changes in production of type 1 and type 2 cytokines and the effects of hormone replacement therapy.

OBJECTIVE: An appropriate defense against infective agents or malignant cells is attributed to the exquisitely balanced T helper 1 type (cellular) and T helper 2 type (humoral) immune reactions. We investigated the effect of hormone replacement therapy (HRT) on postmenopausal changes in the production of interferon (IFN)-gamma and interleukin (IL)-10, a type 1 and a type 2 cytokine, respectively. DESIGN: Both cytokines were measured by ELISA in the supernatant of lipopolysaccharide-stimulated whole blood cells from 72 untreated and 44 HRT-treated women. Thirteen women were examined before and during HRT. RESULTS: The production of IFN-gamma in women in their 40s and in postmenopausal women was significantly higher compared with that of younger women. However, IFN-gamma fell to the lowest level in the late postmenopausal stage, whereas the production of IL-10 increased gradually with age and in parallel with the postmenopausal period. Thus, in women in the mid-and late postmenopausal period, excessive production of type 2 cytokine (IL-10) compared with type 1 cytokine (IFN-gamma) occurred. The IFN-gamma levels of women on HRT were significantly lower than those of untreated women in the early and mid-postmenopausal stages, and IL-10 levels of women on HRT were significantly lower than those of untreated women in the mid-and late postmenopausal stages. HRT induced a significant decrease in the production of IL-10 and tended to lower the level of IFN-gamma. CONCLUSIONS: Production of IL-10 is augmented in postmenopausal women. HRT probably prevents postmenopausal women from an aberration of the immune system by improving the balance of type 1 and type 2 immune reactions.

Absorption of anticancer drugs through bladder epithelium.

Fundamental and clinical evaluations of ten anticancer drugs were performed. The required qualities of an anticancer drug ideal for bladder instillation therapy are thought to be as follows: (1) a high sensitivity for bladder tumor cells; (2) a pKa which provides a high percentage of nonionized molecules in a pH 6-7 solution; (3) a log P in the range from -0.4 to -1.2 or from -7.5 to -8.0; and (4) a molecular weight over 200.

Development and clinical application of an AFC regimen (adriamycin, futraful, cytosine arabinoside) for superficial bladder tumors.

Our AFC regimen was originally developed to treat superficial bladder tumors. It consists of a daily intravesical administration of 20 mg Adriamycin (ADM) and 200 mg Cytosine arabinoside (CA) dissolved in 20 ml of sterilized distilled water, simultaneously with a daily rectal suppository of 750 mg tegafur (Futraful) for a total of 20 applications. Our study demonstrated the following characteristics of the AFC modality: (1) It is simple; (2) it is completed in 3 weeks, which is shorter than conventional bladder instillation therapy; (3) the effective rate is reasonable (70%); (4) no local side-effects were observed because the concentrations of ADM and CA were low; (5) interruption of therapy was unnecessary, because whatever general side-effects were caused, they disappeared within several days of completion of treatment.

Hypothalamic thyrotropin-releasing hormone (TRH)-containing neurons involved in the hypothalamic-hypophysial-thyroid axis. Light microscopic immunohistochemistry.

The localization of neurons containing immunoreactive thyrotropin-releasing hormone (TRH) was examined in the hypothalamus of intact, propylthiouracil (PTU)-treated, and colchicine-treated adult rats. In intact animals, immunoreactive TRH neurons were occasionally found in the paraventricular and dorsomedial nuclei, and in the anterior and lateral hypothalamic areas. In PTU-treated animals, the cellular appearance of the hypothalamus with the exception of the paraventricular nucleus was almost similar to that of intact animals. In the paraventricular nucleus, only the cells localized in the periventricular and medial parvocellular subdivisions significantly increased in number and became hypertrophic in comparison with intact animals. The distribution of immunoreactive fibers in the hypothalamus was almost equal among the 3 animal groups with the exception of that in the median eminence, in which the fibers were most densely concentrated in intact animals, and most sparse in PTU-treated rats. The fibers projecting into the median eminence were distinguished into the periventricular and lateral pathways, which are derived from the neurons in the periventricular and medial parvocellular subdivisions of the paraventricular nucleus, respectively. Thus, among immunoreactive TRH neurons in the hypothalamus, only those in the periventricular and medial parvocellular subdivisions of the paraventricular nucleus may be involved in the hypothalamic-hypophysial-thyroid axis.

Binding of human secretory leukocyte protease inhibitor in uterine cervical mucus to immunoglobulins: pathophysiology in immunologic infertility and local immune defense.

OBJECTIVE: To identify an Fc receptor-like molecule in human cervical mucus. DESIGN: Controlled experimental laboratory study. SETTING: Department of Obstetrics and Gynecology, School of Medicine, University of Tokushima. PATIENT(S): Women undergoing treatment for infertility. INTERVENTION(S): Sodium dodecyl sulfate-polyacrylimide gel electrophoresis and Western blot were used for analysis. MAIN OUTCOME MEASURE(S): A water-insoluble protein with immunoglobulin-binding activity was purified from human cervical mucus by ammonium sulfate fractionation. The initial 21 amino acids of the N-terminus of the immunoglobulin-binding protein were determined and analyzed in a computer search for homology. RESULT(S): The purified fraction contained a 15-kd protein that binds immunoglobulin A, immunoglobulin M, and all subclasses of human immunoglobulin G as determined by Western blot analysis. The amino acid sequence of the N-terminus is identical to that of secretory leukocyte protease inhibitor. The capacity of secretory leukocyte protease inhibitor to bind immunoglobulins was confirmed by Western blot analysis. CONCLUSION(S): A component in human cervical mucus capable of binding immunoglobulins was identified as secretory leukocyte protease inhibitor. The capacity to bind immunoglobulins is a unique property of the protein, providing additional support for the contention that it plays an important physiologic role in local tissue defense mechanisms. It also is involved in the pathogenesis of immunologic infertility by trapping sperm in the cervical mucus.

High implantation rate and consequently high pregnancy rate by in vitro fertilization-embryo transfer treatment in infertile women with antisperm antibody.

OBJECTIVE: To examine the effect of antisperm immunity on postfertilization steps, such as implantation of embryos and fetal growth in IVF-ET treatment of women with sperm-immobilizing antibodies. DESIGN: Retrospective analysis of clinical laboratory data. SETTING: The IVF-ET program of the Department of Obstetrics and Gynecology. The University of Tokushima, School of Medicine. PATIENTS: Eighteen women with sperm-immobilizing antibodies and 122 infertile patients with nonimmune etiology as controls. Infertile couples due to a male factor and with unknown etiology were excluded. INTERVENTIONS: All patients received the same IVF-ET program with GnRH agonist. MAIN OUTCOME MEASURES: Rates of fertilization and cleavage, implantation rate per embryo transferred and pregnancy rate (PR) in both test and comparison groups. RESULTS: The rate of fertilization in the antisperm group (61.3%) was significantly lower than that in the comparison group (76.8%). But the implantation rate per embryo transferred (23.5%) and consequently the modified PR per oocyte recovery procedure (34.4%) in immunologically infertile women were significantly higher than those in the comparison group (7.9% and 17.8%, respectively). CONCLUSIONS: Although sperm-immobilizing antibodies prevent sperm-egg interaction, they do not seem to have any adverse effects on achievement of pregnancy. Moreover, the existence of antisperm immunity in woman with antisperm antibodies is suggested to be favorable for successful pregnancy by the IVF-ET procedure.

Quality of embryo does not affect the implantation rate of IVF-ET in infertile women with antisperm antibody.

OBJECTIVE: To determine whether low quality score of embryos and advanced maternal age affect the implantation rate in infertile women with sperm-immobilizing antibody. DESIGN: A retrospective study. SETTING: The IVF Unit of the Department of Obstetrics and Gynecology at Tokushima University Hospital. PATIENT(S): Four infertile groups were studied: 20 women with sperm-immobilizing antibodies; 169 with tubal; 129 with male factor; and 72 with unexplained etiology. INTERVENTION(S): All women were hyperstimulated with GnRH analogue and scheduled ovarian stimulation with FSH and hMG for oocyte retrieval. MAIN OUTCOME MEASURE(S): Relationship of quality of transferred embryos, implantation rate and maternal age among four groups of infertile couples. RESULT(S): In the antisperm group, the fertilization rate (57.6%) and mean (+/- SD) score of transferred embryos (5.4+/-1.9) were significantly lower than those in the tubal group (72.4% and 6.2+/-1.9, respectively). However, the implantation rate in the antisperm group (23.6%) was significantly higher than those in other three groups (tubal, 8.6%; male factor, 9.5%; unexplained, 7.6%). With advancing maternal age, the implantation rate decreased in the three comparative groups. In contrast, the implantation rate in the antisperm group did not decrease with advancing maternal age. CONCLUSION(S): Women with antisperm antibodies have several disadvantages to overcome in order to achieve successful IVF-ET, such as a low fertilization rate and poor quality of transferred embryos. However, a high implantation rate was observed in this group, even in women at advanced age. The occurrence of a cellular or humoral immune reaction against sperm may augment the uterine receptivity for the implantation of fertilized ova or blastocyst.

Identification of the human sperm protein that interacts with sperm-immobilizing antibodies in the sera of infertile women.

OBJECTIVE: To identify the target antigen of sperm-immobilizing antibodies present in the circulation of infertile women. DESIGN: Laboratory research. SETTING: Academic research laboratory. PATIENT(S): Twenty-nine infertile women with sperm-immobilizing antibodies, 22 infertile women with other disorders, and 20 fertile women. INTERVENTION(S): Titers of antibodies to the sperm protein, rSMP-B, were determined by ELISA using as substrate the synthetic peptide segment (rSMP-230) that corresponds with the hydrophilic domain of rSMP-B. Tests for sperm immobilization and zona pellucida penetration were performed using the human IVF system. MAIN OUTCOME MEASURE(S): Human sera with sperm-immobilizing activity were assayed for the presence of antibodies to rSMP-230. Polyclonal antibodies to rSMP-230 were assessed for the same biologic activities as sperm-immobilizing antibodies. RESULT(S): Antibodies to rSMP-230 were detected in 10 (34%) of 29 sera obtained from women with immunologic infertility. In contrast, only one serum sample (2%) from women without sperm-immobilizing activity had a low titer of antibodies to rSMP-230. Polyclonal antibodies to rSMP-230 completely immobilized human sperm in the presence of complement and blocked sperm penetration across the zona pellucida. CONCLUSION(S): The human sperm protein, rSMP-B, probably is the target antigen of sperm-immobilizing antibodies.

Antisperm antibody: a monkey wrench in conception/magic bullet of contraception?

Antisperm antibodies can cause infertility by interacting with spermatozoa through immunoglobulin binding protein thereby blocking their penetrance of cervical mucus and/or by interfering with sperm-egg interaction. However, these antibodies appear not to be cytotoxic to embryos since a high implantation rate and consequently high pregnancy rate were achieved by IVF-ET treatment of women with antisperm antibodies. Also the finding that these antibodies do not appear to cause any deleterious clinical symptoms and have yet be associated with infertility suggested that sperm antigens are promising candidates in the development of immunocontraceptives. Some synthetic peptides corresponding to segments of human sperm antigens have effectively induced infertility in female rats when administered as an immunogen. Different peptides, adjuvants and routes of administration should be studied to determine the optimum conditions for inducing high antisperm antibody titers in the host. Moreover, identification of various steps and factors that are involved in regulating the production of antisperm antibodies such as immunoglobulin binding factor may open new paths in the treatment of immunological infertility and at the same time lead to a more effective immunocontraceptive.

B cell subsets in postmenopausal women and the effect of hormone replacement therapy.

OBJECTIVES: In elderly subjects the capacity for antibody production is depressed. This immunosenescence state of humoral immunity is associated with the occurrence of autoimmune disorders involving CD5+ B (B-1) cells. Since estrogen is capable of stimulating the production of autoantibodies, this sex steroid hormone may be a contributing cause of the higher incidence of autoimmune diseases in women. In the present study, B cell subsets in women during the postmenopausal period was determined. The effect of hormone replacement therapy (HRT) on B cell subsets was examined to establish whether the administration of gonadal hormones influence humoral immunity in postmenopausal women. METHODS: Forty six untreated pre- and postmenopausal women and 39 women on HRT were studied. The proportion of B-1 (CD5+) and conventional CD5- B (B-2) lymphocytes was determined by two-color flow cytometry. Serum autoantibodies to a nuclear antigen and to interleukin (IL)-1alpha were measured by immunofluorescence and by radioimmunoassay, respectively. Thirteen women were examined prospectively before and during HRT. RESULTS: In late postmenopausal women (> or = 30 years postmenopausal period), the proportion of B-2 cells was significantly reduced (p<0.01) compared to those of premenopausal and perimenopausal women. HRT induced a significant (p<0.01) increase in the percentage of B-2 cells, while that of B-1 cells remained unchanged. HRT did not affect autoantibody production. CONCLUSION: HRT may retard the progress of immunosenescence by increasing the production of B-2 cells. Moreover, HRT appears not to increase the risk of autoimmune diseases developing in postmenopausal women.

Immunosuppressive 30-kDa protein in urine of pregnant women and patients with trophoblastic diseases.

Urine samples obtained from normal pregnant women and patients with trophoblastic diseases contain 30-kDa protein that suppresses phytohemagglutinin-induced T cell proliferation. The immunosuppressive protein was measured by a newly developed radioimmunoassay. The 30-kDa protein was demonstrated in almost all urine samples examined, fluid from hydatid vesicles and chorionic extracts, but not in any serum samples except at low levels in some sera from patients with choriocarcinoma. During pregnancy, the level of urinary 30-kDa protein was higher in the first (1625.5 +/- 1212.0 ng/ml, mean +/- S.D.) and second (1457.4 +/- 1332.4 ng/ml) trimesters than in the third trimester (460.6 +/- 419.0 ng/ml). The urinary 30-kDa protein/hCG ratios in patients with choriocarcinoma (8.3 +/- 10.9) were significantly higher than those in patients with hydatidiform mole (0.67 +/- 1.00, P < 0.01) and in all trimesters than those of normal pregnant women (0.54 +/- 0.44 in first trimester, P < 0.05; 0.63 +/- 0.46 in the second trimester, P < 0.05; 0.24 +/- 0.17 in the third trimester, P < 0.01). There is no significant difference between the ratios in hydatidiform mole and normal pregnancy. These findings and the fast disappearance of the 30-kDa protein from the circulation suggest that the 30-kDa protein plays a part in proliferation of trophoblastic cells in, or their invasion into the host by locally suppressing the immune reaction of the host and that the increase in the urinary 30-kDa protein level, in cases of choriocarcinoma, may be due to the malignant transformation of trophoblastic cells resulting in their rapid invasion.

[Clinical evaluation of M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) chemotherapy for advanced urothelial cancer].

M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) chemotherapy was performed on 27 patients with advanced urothelial cancer. The patients included 20 with bladder cancer, 4 with upper urinary tract cancer and 3 with both lesions. Complete response (CR) was observed in 2 (7.4 +/- 9.9%) patients and partial response (PR) in 10 (37.0 +/- 18.2%) patients after the treatment, i.e., the overall objective response rate was 44.4 +/- 18.7%. The rate of relapse or recurrence in the patients with CR and PR was 100% and 90.0%, respectively. The mean duration of the response was 18.5 +/- 13.4 months and 10.7 +/- 10.9 months for CR and PR, respectively. The overall survival rate after one year was 30.2%. Bone marrow suppression was the most serious side effect. The white blood cell count became below 1,000/microliters in 10 patients (36.7%). Among them, 4 patients suffered from sepsis. In conclusion, M-VAC chemotherapy was effective for induction therapy against advanced urothelial cancer, although the effective duration was short. Further maintenance therapy should be established.

[The usefulness of autologous blood transfusion for urologic surgery].

To avoid potential risks associated with homologous blood transfusion including viral infection and graft versus host disease (GVHD), autologous blood donations have been promoted in urologic surgery. We assessed its necessity in the patients undergoing radical retropubic prostatectomy and total cystectomy. A total of 27 patients ranging from 54 to 78 years old donated 400 to 1,200 ml of blood prior to radical prostatectomy (17 patients) and total cystectomy (10 patients). Recombinant erythropoietin was administered in 26 out of 27 patients. The mean hemoglobin concentration was 14.1 g/dl before donation and 12.8 g/dl before operation. The mean volume of surgical blood loss was 1,659 ml ranging from 529 to 2,990 ml in total cystectomy, and 1,438 ml ranging from 553 to 2,841 ml in radical prostatectomy. Overall, 22 out of 27 patients (82%) did not require an additional homologous blood transfusion. In conclusion, autologous blood donation is a safe and useful method to avoid homologous transfusion in radical prostatectomy and total cystectomy. Eight hundred ml of blood donation is suggested to be appropriate prior to these surgeries.

[Clinical evaluation on renal pelvic and ureteral tumors].

We report 82 patients with renal pelvic and ureteral tumors admitted to Kyoto Prefectural University of Medicine, Kyoto Second Red Cross Hospital and Shakai-Hoken Kyoto Hospital between January, 1981 and December, 1991. Sixty two were males and 24 were females, and they were between 47 and 93 years old (average: 68.2 years). The tumor occurred on the right side in 34 patients, on the left side in 51 patients and on both sides in one patient. There were 43 renal pelvic tumors, 37 ureteral tumors and 6 renal pelvic with ureteral tumors. The most frequent symptom was macrohematuria, which was seen in 54 patients (62.8%). Urinary cytology was performed in 76 patients and a positive result was obtained in 44 patients (57.9%). We performed surgical treatment on 71 patients. The most frequently adopted method was total nephroureterectomy with partial cystectomy which was performed on 51 patients (71.8%). Of the 73 specimens diagnosed histopathologically, 71 specimens were transitional cell carcinoma (TCC), one was a squamous cell carcinoma (SCC) and one was a mixed type of TCC and adenocarcinoma. As to grading, 6 specimens were G1, 28 G2, 38 G3 and one GX. As to staging, 8 specimens were pTa, 17 pT1, 21 pT2, 18 pT3, 8 pT4 and one pTX. The overall survival rate (by Kaplan-Meier's method) at 3 and 5 years was 47.0% and 39.5%, respectively. The patients with high grade tumors and those who had ureter preservation, the survival rate was lower than in the other patients.

[Intermittent androgen deprivation treatment of prostate cancer restarted at low level of serum prostate specific antigen: a pilot study].

We report a pilot study on a novel protocol of intermittent androgen deprivation (IAD) treatment of prostate cancer (PC), in which androgen deprivation is restarted when serum prostatic specific antigen (PSA) level reached more than 2 ng/ml and is stopped when PSA level decreased below 0.3 ng/ml. Thirty-two patients (aged 60 to 86 years, median 74 years) with prostate cancer (Stage A in 4 patients, B in 20, C in 1, D in 5, and relapse after radical prostatectomy in 2) were treated with IAD. Median serum PSA prior to the start of endocrine therapy was 15.65 (range 2.67 to 306.3) ng/ml. Eleven patients were treated with lutenizing-hormone-releasing hormone (LHRH) agonist alone and 21 were treated with LHRH agonist plus an antiandrogen. Median duration of first endocrine therapy was 572 (range 100 to 1,543) days. Median serum PSA at the start of first off-phase was 0.038 (range 0.003 to 0.489) ng/ml. After a median of 207 days (range 140 to 843) of follow-up, 19 patients were in the first cycle, 9 in the second cycle, 3 in the third cycle, 1 in the fourth cycle. Two patients developed androgen-independent PC. The median duration of first off-phase of IAD was 287 days. There was a significant inverse relation between the duration of the first on-phase and testosterone level measured 4 months after the cessation of first on-phase therapy (R = -0.518). These results suggest that our protocol provides a reasonable length of off-phase duration and that the long term-androgen deprivation phase might delay the recovery of the testicular endocrine function which should be maintained during the off-phase of IAD.