Prevention of the initial testosterone surge induced by a luteinizing hormone-releasing hormone analogue in prostate cancer patients:the endocrinological effects of pretreatment with chlormadinone acetate

Prevention of the initial testosterone surge induced by a luteinizing hormone-releasing hormone analogue in prostate cancer patients:the endocrinological effects of pretreatment with chlormadinone acetate

Akihiro Yamamoto, Yoshiteru Sumiyoshi^a, Noriaki Miyake^a^a, Hideaki Yokozeki^b,
Hiro-omi Kanayama^c, and Susumu Kagawa^c

Department of Urology, Kochi Takasu Hospital, Kochi, Japan;^aDepartment of Urology, National Shikoku Cancer Center Hospital, Ehime, Japan;**Department of Urology, Yashima General Hospital, Kagawa, Japan;^bDepartment of Urology, Tokushima Municipal Hospital, Tokushima, Japan;and ^cDepartment of Urology, The University of Tokushima School of Medicine, Tokushima, Japan

Abstract:We investigated the endocrinological effects of pretreatment with chlormadinone acetate (CMA) in preventing the initial testosterone surge induced by a luteinizing hormone-releasing hormone (LH-RH) analogue. A total of 25 patients with previously untreated prostate cancer were included in this study. The patients were randomly assigned to 2 treatment groups:Group1;CMA therapy was begun 4 weeks before the initial LH-RH analogue injection. Group 2;CMA therapy was begun 2 weeks before the initial LH-RH analogue injection. After the initial LH-RH analogue injection, CMA was administered during this study. After LH-RH analogue application, the mean values of serum luteinizing hormone (LH) and testosterone increased in both groups on day 3. However, LH and testosterone levels remained beneath pretreatment values in both groups. The mean relative PSA levels did not significantly increased on day 3 and day 7in both groups. Our results indicate that pretreatment with CMA for 2 weeks was sufficient to prevent the initial testosterone surge in the maximal androgen blockade which was associated with CMA. J. Med. Invest. 46:55-58, 1999

Keywords:Prostate cancer, Luteinizing hormone-releasing hormone analogue, Disease flare, Chlormadinone acetate

INTRODUCTION
The luteinizing hormone-releasing hormone (LH-RH) analogue induces a transient release of luteinizing hormone (LH) with a consecutive in-crease in testosterone, and this increase results in exacerbation of clinical signs and symptoms in some prostate cancer patients [1, 2]. Several studies have demonstrated that this disease flare can be effec-tively eliminated by the use of antiandrogens in combination with or before initiation of LH-RH analogue therapy [3-6]. However, the optimal duration of pretreatment is rather difficult to deter-mine. We herein report the endocrinological effects of pretreatment with the steroidal antiandrogen, chlormadinone acetate (CMA ; 6-chloro-3,20-dioxo-4,6-pregnadien-17-yl acetate, Teikoku Hormone MFG Co. Tokyo, Japan) for the prevention of this initial testosterone surge.

PATIENTS AND METHODS
A total of 25 patients with previously untreated prostate cancer (stage B, C, D) proved by biopsy were included in this study. All patients gave informed consent to participate in the study. The patients were assigned randomly to 2treatment groups. Group1 patients were treated with the depot LH-RH ana-logue (leuprorelin acetate 3.75mg or goserelin3.6mg) plus CMA. CMA therapy was begun 4weeks before the initial LH-RH analogue injection at a dosage of 100mg/day orally. Group 2 patients were treated with the LH-RH analogue plus CMA at the same dosages used in group 1with the exception that CMA therapy was begun 2weeks before the initial LH-RH analogue injection. After the initial LH-RH analogue injection, CMA was administered to both groups.
Serum LH, testosterone, and prostate specific antigen (PSA) were measured in each patient before the initial CMA administration, and on days 0, 3, 7,and 28 of LH-RH analogue therapy. Serum LH (Spack-S LH kit, Daiichi Radioisotope Laboratories Ltd., Tokyo, Japan) and testosterone (Total Testos-terone, Diagnostic Products Corporation, Los Angels, USA) levels were measured by radioimmunoassay. PSA assay was performed by the monoclonal Hybritech Tandem-R immuno-radiometric technique (Tandem-R PSA, Hybritech. Inc., San Diego, USA). Due to the wide variation of the initial values of serum PSA, we investigated the mean relative PSA levels. Relative values were expressed as a percentage of the initial value for each patient before therapy started, which was considered100%.
Histologically, differentiation of adenocarcinoma was evaluated according to the criteria of the General Rules for Clinical and Pathological Studies on Prostatic Cancer [7]. Data are presented as means±SD (standard deviation). For statistical analysis, the Wilcoxon one sample analysis, paired Wilcoxon test and Mann-Whitney U test were used and a P value below 0.05 was considered to indicate statistical significance.

RESULTS
The characteristics of the patients are shown in table1. There were no significant differences be-tween the 2 treatment groups in the initial age, histopathological grade, clinical stage, serum LH, testosterone and PSA levels at the start of treat-ment.
The mean absolute values of serum LH and tes-tosterone in both groups are shown in figures 1and 2. Pretreatment with CMA decreased serum LH levels. Compared to day 0 (the initial injection of the LH-RH analogue), the serum LH levels were increased on day 3 (Group 1;2.83±2.22 vs. 4.06±2.05mIU/ml, Group2;4.92±3.61 vs. 7.95±5.23mIU/ml), and then decreased. However, the serum LH levels on day 3 did not reach pretreatment levels in either group. There were no significant differ-ences in serum LH levels between the groups on days0, 3, 7, and 28. The serum testosterone levels showed a parallel decrease with LH until day 0,and reached castration levels below 100ng/dl in both groups. Temporary increases were observed on day3 (Group1;138.12±95.82ng/dl, Group2;202.58±81.70ng/dl), but did not reach pretreat-ment levels. On day 7, serum testosterone levels decreased to castration levels in both groups. There were no significant differences in serum testosterone levels between the groups on days 0, 3, 7, and28.
The mean relative values of serum PSA are shown in figure3. CMA pretreatment significantly reduced serum PSA. On day 0, the mean relative values of serum PSA in group 2 (45.31±24.76%) were higher than those in group1 (24.92±11.89%). There were no significant differences among the groups on days 3, 7, and28. In group2, the mean relative values of serum PSA were significantly lower on day3 (38.26±19.71%) and day7 (35.25±19.62%) than on day0(45.31±24.76%). However, the mean relative PSA levels were not lower on day3 (25.26±12.34%) or day 7 (27.68±12.31%) than on day 0 (24.92±11.89%) in group 1. In 3 cases in group 1, the mean relative values of serum PSA decreased in a linear fashion after the initial injection of the LH-RH ana-logue, and all 3cases exhibited well differentiated adenocarcinoma. In contrast, increases in the mean relative values of serum PSA on day7compared to days 0 or 3 were observed in 9 cases. The adeno-carcinoma was well differentiated in 1 case, mod-erate in 5, and poor in 3. Increases in the mean relative values of serum PSA on day 7were more frequently seen in the patients with high histopatho-logical grade (p<0.05). There was no correlation between the change in mean relative values of serum PSA and the clinical stage.
No signs or symptoms of disease flare were ob-served in either group.

DISCUSSION
Since disease flare is considered to be due to the initial increase in serum testosterone, the use of antiandrogens in combination with or before ini-tiation of a LH-RH analogue has been advocated. Labrie et al. [3] reported that the concomitant administration of the nonsteroidal antiandrogen, flutamide, completely eliminated the risk of disease flare. On the other hand, Schulze et al. [4] indicated that pretreatment with flutamide for only 1 day may not be sufficient to prevent tumor flare, and should begin 1 week before the LH-RH analogue injection. However, from an endocrinological viewpoint, the effects of nonsteroidal antiandrogens in preventing disease flare are rather difficult to determine due to their mode of action [6]. Pretreatment with the steroidal antiandrogen, cyproterone acetate, for1week prevented the LH-RH analogue induced tes-tosterone surge and an initial increase in prostatic acid phosphatase beyond the pretreatment levels[4]. The administration of estramustine phosphate560mg daily for 3weeks prior to goserelin acetate depot therapy was also considered sufficient to prevent tumor flare [6].
The steroidal antiandrogen CMA was reported to reduce serum testosterone levels and block the binding of androgens to androgen receptors in prostatic carcinoma tissue [8]. Nishimura et al. [9]reported that the plasma testosterone concentration decreased to levels of normal females after 4-6weeks of CMA administration, but increased to an average level of 109ng/dl after 8 -10weeks of CMA administration. Yoshida et al. [5] investigated the efficacy of 2-week and 4-week pretreatment with100mg/day CMA to prevent disease flare in patients with metastatic carcinoma of the prostate. Since serum PSA levels significantly increased in the2-week pretreatment group but showed a linear decrease in the 4-week pretreatment group, they concluded that the 4-week regimen was more effec-tive than the 2-week regimen [5]. However, there are two major differences from our study. First, CMA was discontinued after the LH-RH analogue therapy in their study. Second, they investigated the efficacy in patients with metastatic carcinoma of the prostate.
In recent meta-analyses, maximal androgen blockade (MAB) continues to be debated, with ad-vocates both for and against its efficacy [10, 11]. In the present study, CMA was continued after the LH-RH analogue therapy for the purpose of MAB. The serum LH and testosterone levels were in-creased on day 3 compared to day 0, but did not reach pretreatment levels in either group. The mean relative values of serum PSA were significantly lower on day 3 and day 7 than on day 0 in group 2. However, the mean relative PSA levels were not lower on days 3 or 7 than on day 0 in group1, de-spite the longer pretreatment. These results suggest that pretreatment for 2 weeks is sufficient to pre-vent the initial testosterone surge in the MAB which is associated with CMA. PSA change induced by a transient testosterone increase may be different in each case, and it seems to be difficult to identify the correlation factor. However, as shown in our results the histopathological grade may contribute to the difference. A larger prospective trial is necessary to elucidate this factor.

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Received for publication November 17, 1998 ; accepted December 25, 1998.

Address correspondence and reprint requests to Dr. Akihiro Yamamoto, Department of Urology, Kochi Takasu Hospital, Takasu-shin-machi, Kochi 780-8122, Japan and Fax:+81-888-84-1892.